Method of treatment of androgen-related diseases

ABSTRACT

A method of treatment of androgen-related diseases such as prostate cancer in susceptible male animals, including humans, comprises administering novel antiandrogens and/or novel sex steroid biosynthesis inhibitors as part of a combination therapy. Sex steroid biosynthesis inhibitors, especially those capable of inhibiting conversion of dehydroepiandrosterone (DHEA) or 4-androstenedione (Δ 4  -dione) to natural sex steroida (and testosterone into dihydrotestosterone) in peripheral tissues, are used in combination with antiandrogens usually after blockade of testicular hormonal secretions. Antiestrogens can also be part of the combination therapy. Pharmaceutical compositions and two, three, four and five component kits are useful for such combination treatment.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.07/376,710 filed Jul. 7, 1989 now abandoned, which is acontinuation-in-part of U.S. patent patent application Ser. No.07/322,154, filed Mar. 10, 1989 entitled: "INHIBITORS OF SEX STEROIDBIOSYNTHESIS AND METHODS FOR THEIR PRODUCTION AND USE", now abandonedthe entire disclosure of which is hereby incorporated by reference asthough fully set forth herein.

BACKGROUND OF THE INVENTION

This invention relates to a method of treatment of androgen-relateddiseases such as prostate cancer in warm-blooded male animals (includinghumans) in need of such treatment, and in particular, to a combinationtherapy comprising administering an antiandrogen in association with aninhibitor of sex steroid biosynthesis to such animals. The inventionalso includes pharmaceutical compositions and kits useful for suchtreatment. Androgen-dependent diseases include diseases whose onset,maintenance or progress is, at least in part, dependent upon biologicalactivities induced by androgens (e.q. testosterone anddihydrotestosterone). In one embodiment, the invention provides atreatment of hormone-dependent prostate cancer in warm-blooded maleanimals which comprises administering both an antiandrogen and at leastone inhibitor of sex steroid biosynthesis capable of inhibitingconversion of dehydroepiandrosterone or 4-androstenedione to natural sexsteroids in extra-testicular and extra-adrenal tissues.

While various investigators have been studying hormone-dependentprostate cancer, none have proposed the combination therapy of thisinvention.

A. V. Schally et al., Cancer Treatment Reports, 68 (No. 1) 281-289(1984), summarize the results of animal and clinical studies on growthinhibition of hormone-dependent mammary and prostate tumors by use ofanalogues of luteinizing hormone-releasing hormones, the so-called LHRHagonists and suggest that LHRH analogs and/or antagonists may havepotential for treating breast cancer.

T. W. Redding and A. V. Schally, Proc. Natl Acad. Sci. UA 80, 1459-1462(1983), relates to inhibition of prostate tumor growth in rats bychronic use of an LHRH agonist, [D-Trp⁶ ]LHRH.

U.S. Pat. No. 4,329,364 relates to use of the antiandrogen,4'-nitro-3'trifluoromethyl isobutyranilide for treatment of prostaticcancer.

U.S. Pat. No. 4,472,382 relates to treatment of prostate adenocarcinoma,benign prostate hypertrophy and hormone-dependent mammary tumors maywith various LHRH agonists and treatment of prostate adenocarcinoma andbenign hypertrophy by use of various LHRH agonists and an antiandrogen.

U.S. Pat. No. 4,659,695 (Labrie) relates to treatment of prostate cancerin animals whose testicular hormonal secretions are blocked. The methodof treatment includes administering an antiandrogen such as flutamide asan inhibitor of sex steroid biosynthesis such as aminoglutethimideand/or ketoconazole.

Some clinical improvement in men with prostate cancer by use of the twoLHRH agonists, Buserelin and Leuprolide, is also reported by N. Faure etal. at pages 337-350 and by R. J. Santen et al. at pages 351-364,respectively, LHRH and its Analogues--A new Class of Contraceptive andtherapeutic Agents (B. H. Vickery and J. J. Nestor, Jr., and E. S. E.Hafez, eds), Lancaster, MTP Press, (1984).

R. Santen et al., The Journal of Steroid Biochemistry, volume 20, no.6B, at page 1375 (1984), relates that the use of ketoconazole incombination with chronic administration of Leuprolide in rodentsdecreased basal and Leuprolide-stimulated testosterone levels.

One of Applicant's Co-pending U.S. patent application Ser. No.07/321,926 filed Mar. 10, 1989, relates to a combination therapy fortreatment of estrogen-related diseases by inhibiting ovarian hormonalsecretions and administering an antiestrogen in combination with atleast one of several enumerated activity blockers, sex steroid formationinhibitors and the like.

D. Kerle et al., The Journal of Steroid Biochemistry, volume 20, no. 6B,at page 1395 (1984) relates to the combined use of a LHRH analogue andketoconazole producing objective responses in some prostate cancerpatients who have relapsed or failed to respond to treatment with a LHRHanalogue alone.

F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that use ofa combination therapy of an LHRH agonist (Buserelin) and an antiandrogen(Anandron) to treat advanced prostate cancer in previously untreatedpatients effects simultaneous elimination of androgens of bothtesticular and adrenal origin.

F. Labrie et al., J. Steroid Biochem., 19, 999-1007 (1983), disclose thetreatment of prostate cancer by the combined administration of an LHRHagonist and an antiandrogen. Labrie et al. disclose animal and clinicaldata in support of the proposition that the combined LHRH/antiandrogentreatment neutralizes the stimulatory influence of all androgens on thedevelopment and growth of androgen-dependent prostatic cancer.

F. Labrie et al., Abstracts of the 7th International Congress ofEndocrinology, Excerpta Medica (1984) at page 98 disclose that treatmentof prostate cancer patients with LHRH agonists alone causes a transientincrease in serum androgen levels lasting for 5 to 15 days beforecastration levels are reached. While F. Labrie et al. recommend thatorchiectomy, estrogen and LHRH agonists alone should not be further usedfor treatment of prostate cancer in the absence of a pure antiandrogen,there still is a need for a method of treatment of prostate cancer thateffects more complete androgen blockage at the start as well as duringthe full period of treatment.

There are many data indicating that estrogens have a stimulatory effecton prostatic growth (Lee et al., 1981; J. Androl. 2:293-299; Belis etal., 1983; J. Androl. 4: 144-149; Walsh and Wilson, 1976; J. Clin.Invest. 57: 1093-1097; De Klerk et al., 1985; Prostate 7, 1-12;Habesucht et al., 1987; Prostate 11: 313-326). Estrogens have also beenfound to enhance the growth-promoting effect of androgens (Farnsworth,1969; Invest. Urol. 6: 423-427; Groom et al., 1971; Biochem. J. 122:125-126; Lee et al., 1973; Steroids 22: 677-683).

Estrogen receptors have been demonstrated in human normal, hyperplasticand cancer prostatic tissue (Mobbs et al., 1989; Proc. 84th EndocrineSoc., Meeting, abst. No. 1410; Mobbs et al., 1983; J. Steroid Biochem.19, 1279-1290; Wagner et al., 1975; Acta Endocrinol. (Kbh), suppl. 193,52; and also in laboratory animal prostatic tissue (Swaneck et al.,1982; Biochem. Biophys. Res. Commun. 106: 1441-1447).

Moreover, androgen receptor levels were found to be elevated inprostatic tissue of patients treated with estrogen, thus indicating astimulatory effect of estrogen on the level of androgen receptors inprostatic tissue (Mobbs et al., 1983; J. Ster. Biochem. 19, 1279-1290).A similar stimulatory effect of estrogen has been observed in the dogprostate (Moore et al., 1979; J. Clin. Invest. 63, 351-357).

In the prostate as well as in many other tissues, testosterone isirreversibly converted by 5α-reductase into the more potent androgendihydrotestosterone (Bruchovsky and Wilson, J. Biol. Chem. 243:2012-2021, 1968; Wilson, Handbook of Physiology 5 (section 7), pp.491-508, 1975). Inhibitors of 5α-reductase have been found to inhibitprostatic growth (Brooks et al., Endocrinology 109: 830, 1981; Brooks etal., Proc. Soc. Exp. Biol. Med. 169: 67, 1982; Brooks et al., Prostate3: 35, 1982; Wenderoth et al., Endocrinology 113, 569-573, 1983;McConnell et al., J. Urol. 141: 239A, 1989); Stoner, E., Lecture on therole of 5α-reductase inhibitor in benign prostatic hypertrophy, 84th AUAAnnual Meeting, Dallas, May 8th, 1989.

The inhibitory effect of the 5α-reductase inhibitor Merck L. 652,931 onprostatic and seminal vesicle development in the prepubertal rat wasdescribed in Proc. 71st Annual Meeting of Endocrine Society, abst.#1165, p. 314, 1989. The inhibitory effect of MK-906 ondihydrotestosterone formation in men has been described in men byGormley et al., in Proc. 71st Annual Meeting of Endocrine Society, abst.#1225, p. 329, 1989; Imperato-McGinley et al., in Proc. 71st AnnualMeeting of Endocrine Society, abst. #1639, p. 432, 1989; Geller andFranson, in Proc. 71st Annual Meeting of Endocr. Soc., abst. #1640p.432, 1989, and Tenover et al., in Proc. 71st Annual Meeting of Endocr.Soc., abst. #583, p. 169, 1989. The activity of the 5α-reductaseinhibitorsN,N-diethyl-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide (4-MA)and 6-methylene-4-pregnene-3,20-dione (LY207320) has been described byToomey et al., Proc. 71st Annual Meeting of Endocr. Soc., abst. #1226,p. 329, 1989.

BRIEF DESCRIPTION OF THE DRAWING

There is shown in FIG. 1 a schematic representation of the site(s) ofaction of various drugs, enzymes and hormones. The followingabbreviations are used: ER: estrogen receptor; AR: androgen receptor;DHEA: dehydroepiandrosterone.; Δ⁵ -diol: adrost-5-ene-3β, 17β-diol; Δ⁴-dione; androstenedione; DHT: dihydrotestosterone; Anti-A: antiandrogen;Anti-E: antiestrogen; ARO: aromatase; 3β-HSD: 3β-hydroxysteroiddehydrogenase, Δ⁵ -Δ⁴ isomerase; 17β-HSD: 17β-hydroxysteroiddehydrogenase; 1: antiandrogen; 2: inhibitor of 5α-reductase activity;3: inhibitor of 17β-hydroxysteroid dehydrogenase activity; 4:antiestrogen; 5: inhibitor of aromatase activity; 6: inhibitor of 3βactivity.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide combination therapyfor the treatment of prostate cancer wherein the treatment selectivelyinhibits the formation and/or action of hormones which would otherwisecontribute to tumor growth.

It is another object of the invention to provide combination therapyhaving increased effectiveness in slowing or reversing tumor growth.

It is another object of the invention to provide therapy for treatingprostate cancer having significantly reduced frequency of unwanted sideeffects.

It is a further object of the invention to provide kits having aplurality of active ingredients (with or without diluent or carrier)which, together, may be effectively utilized for carrying out the novelcombination therapies of the invention.

It is another object of the invention to provide a novel pharmaceuticalcomposition which is effective, in and of itself, for utilization in abeneficial combination therapy because it includes a plurality of activeingredients which may be utilized in accordance with the invention.

In one aspect, the present invention provides a method for treatingprostate cancer in humans or other warm-blooded animals in need of suchtreatment, said method comprising the steps of blocking androgenreceptors by administering a therapeutically effective amount of anantiandrogen having as part of its molecular structure a substituted orunsubstituted androgenic nucleus of the formula: ##STR1## saidantiandrogen having as another part of its molecular structure at leastone side chain represented by the formula:

--R¹ [--B--R² --]_(x) L--G wherein said side chain is substituted ontosaid androgenic nucleus at a position selected from the group consistingof 6α, 7α, 14α, 15α, 16α, 17α and 17β, and wherein:

x is an integer from 0 to 6, wherein at least one of L and G is a polarmoiety distanced from said ring carbon by at least three interveningatoms, and wherein:

R¹ and R² are independently either absent or selected from the groupconsisting of straight- or branched-chain alkylene, straight- orbranched-chain alkynylene, straight- or branched-chain alkenylene,phenylene and fluoro-substituted analogs of the foregoing;

B is either absent or selected from the group consisting of --O--,--S--, --Se--, --SO--, --SO₂ --, --NR³ --, --SiR³ ₂ --, --CR³ OR³ --,--NR³ CO--, --NR³ CS--, --CONR³ --, --CSNR³ --, --COO--, --COS--,--SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R³ being hydrogen orlower alkyl);

L is either a moiety which together with G, forms a heterocyclic ringhaving at least one nitrogen atom or is selected from the groupconsisting of lower alkyl, --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵CS--, --NR⁵ CONR⁴ -- NR⁶ --NR⁵ C--NR⁴ --, --SO₂ NR⁴ --, --CSS--,--SCS--, --(NO)R⁴ --, --(PO)R⁴ --, --NR⁵ COO--, --NR⁵ SO₂ --, --O--,--NR⁴ --, --S--, --SO-- and --SO₂ -- (R⁴ and R⁵ being independentlyselected from the group consisting of hydrogen and lower alkyl; and R⁶being selected from the group consisting of hydrogen, nitrile andnitro); and

G is either a moiety which together with L forms a heterocyclic ringhaving at least one nitrogen atom or is selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C₃-C₇)cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl, fluoro-substituted analogs of theforegoing,

said method of treatment further comprising the step of inhibiting sexsteroid formation by administering a therapeutically effective amount ofat least one sex steroid formation inhibitor.

In another aspect, the present invention provides a method for treatmentof prostate cancer in a human or other warm-blooded animal in need ofsuch treatment, said method comprising the steps of inhibiting sexsteroid formation by administering a therapeutically effect of amount ofan inhibitor of sex steroid formation capable of blocking formation ofnatural sex steroids from dehydroepiandrosterone and from4-androstenedione in peripheral tissues (extra-adrenal andextra-testicular), or an inhibitor of sex steroid formation having aspart of its molecular structure a substituted or unsubstitutedsex-steroid nucleus, and, as another part of its molecular structure atleast one side chain of the formula

--R¹ [--B--R² --]_(x) L--G substituted onto a ring atom of said sexsteroid nucleur wherein:

x is an integer from 0 to 6, wherein at least one of L and G is a polarmoiety distanced from said ring carbon by at least three interveningatoms, and wherein:

R¹ and R² are independently either absent or selected from the groupconsisting of straight- or branched-chain alkylene, straight- orbranched-chain alkynylene, straight- or branched-chain alkenylene,phenylene and fluoro-substituted analogs of the foregoing;

B is either absent or selected from the group consisting of --O--,--S--, --Se--, --SO--, --SO₂ --, --NR³ --, --SiR³ ₂ --, --CR³ OR³ --,--NR³ CO--, --NR³ CS--, --CONR³ --, --CSNR³ --, --COO--, --COS--,--SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R³ being hydrogen orlower alkyl);

L is either a moiety which together with G, forms a heterocyclic ringhaving at least one nitrogen atom or is selected from the groupconsisting of lower alkyl, --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵CS--, --NR⁵ CONR⁴ -- ##STR2## --SO₂ NR⁴ --, --CSS--, --SCS--, --(NO)R⁴--, --(PO)R⁴ --, --NR⁵ COO--, --NR⁵ SO₂ --, --O--, --NR⁴ --, --S--,--SO-- and --SO₂ -- (R⁴ and R⁵ being independently selected from thegroup consisting of hydrogen and lower alkyl; and R⁶ being selected fromthe group consisting of hydrogen, nitrile and nitro); and

G is either a moiety which together with L forms a heterocyclic ringhaving at least one nitrogen atom or is selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C₃-C₇)cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl, fluoro-substituted analogs of theforegoing;

said method of treatment further comprising administering atherapeutically effective amount of an antiandrogen.

In another aspect, the present invention provides a method for treatingprostate cancer in a human or other warm-blooded animal in need of suchtreatment, said method including the steps of administering atherapeutically effective amount of an inhibitor of 5α-reductaseactivity and administering a therapeutically effective amount of anantiandrogen.

In another aspect, the present invention provides a method for treatingprostate cancer in a human or other warm-blooded animal in need of suchtreatment, said method including the steps of administering atherapeutically effective amount of an inhibitor of 17β-hydroxysteroiddehydrogenase and administering a therapeutically effective amount of anantiandrogen.

In another aspect, the present invention provides a method for treatingprostate cancer in a human or other warm-blooded animal in need of suchtreatment, said method including the steps of administering an effectiveamount of an antiandrogen and at least one sex steroid formationinhibitor from the groups consisting of inhibitors of extragonadal andinhibitors of extraadrenal sex steroid formation.

The invention also provides kits or single packages combining two ormore active ingredients useful in treating prostate cancer. A kit mayprovide (alone or in combination with a pharmaceutically acceptablediluent or carrier), an antiandrogen and at least one additional activeingredient (alone or in combination with diluent or carrier) selectedfrom the group consisting of an LHRH agonist or LHRH antagonist, a sexsteroid formation inhibitor (preferably an inhibitor of 5α-reductaseactivity, an inhibitor of 17β-hydroxysteroid dehydrogenase activity oran inhibitor of 3β-hydroxysteroid dehydrogenase activity) and anantiestrogen.

The foregoing active ingredients may also be mixed in any of theforegoing combinations to form pharmaceutical compositions (with orwithout diluent or carrier) which, when administered, providesimultaneous administration of a combination of active ingredientsresulting in the combination therapy of the invention. Preferably, whenLHRH antagonist or agonist is used, it is administered parenterally. Forthis reason, it may be administered separately in instances where theother active ingredients are formulated for oral ingestion.

The term "sex steroid nucleus" includes estrogenic and androgenicnuclei.

As used herein, the term "androgenic nucleus" includes any compoundwhich, in the absence of the side chain substituent specified herein (R¹[--B--R² --]_(x) L--G), is capable of acting as an androgen asdetermined by a weight increase of at least 35 percent over a seven-dayperiod of the ventral prostate of castrated rats treated with thecompound in question (15 milligrams twice daily per 100 grams of bodyweight) versus a control group of castrated rats. Treatment should starton the day of castration. The precise test, other than any parametersset forth in this paragraph, is that reported in Labrie et al., J. Ster.Biochem. 28, 379-384, 1987.

As used herein, the term "estrogenic nucleus" includes any compoundwhich, in the absence of the side chain substituent specified herein (R¹[--B--R² --]_(x) L--G), is capable of acting as an estrogen asdetermined by a weight increase of at least 100 percent over a seven-dayperiod of the uterus of ovariectomized rats treated with the compound inquestion (0.5 mg twice daily per 100 grams of body weight) versus acontrol group of ovariectomized rats. Treatment should start on the dayof castration. The precise test, other than any parameters set forth inthis paragraph, is that reported in Simard et al., Mol. Endocrinol. 2:775-784 (1988).

The following conventions apply to structural formulae set forth herein.Unless specifically designated to the contrary, substituents may haveeither α or β stereochemistry or, where valence permits, may representone substituent in α position and another in β position. Presence ofoptional double bonds are independent of each other. All structuresinclude salts thereof. Atoms of any sex steroid nucleus for which nosubstituent is shown or described may optionally be substituted orunsubstituted so long as such substitution does not prevent the nucleusfrom functioning as a "sex steroid nucleus" as defined herein. Thoseatoms having a defined substituent may optionally be further substitutedby other substituents where their valence permits such furthersubstitution. As used herein, the term "lower", when describing achemical moiety means a moiety having 8 or fewer atoms. For instance, a"lower alkyl" means a C₁ to C₈ alkyl. Any moiety of more than two atomsmay be straight- or branched-chain unless otherwise specified.

The term "sex steroid formation inhibitor" includes both androgen andestrogen formation inhibitors and encompasses any compound whichinhibits the biosynthesis of active sex steroids or their precursors.One mechanism by which sex steroid formation inhibitors act is byblocking enzymes which catalyze production of natural sex steroids (e.g.dihydrotestosterone), 17β-estradiol and androst-5-ene-3β-17β-diol orprecursors to such sex steroids (e.g. androstenedione). Examples of suchsex steroid formation inhibitors are compounds capable of blocking theenzymatic activity of, for example, 5α-reductase, 3β-hydroxysteroiddehydrogenase, 17β-hydroxysteroid dehydrogenase or aromatase.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a preferred aspect, a combination therapy for prostate cancerincludes administering active ingredients effective to inhibit a varietyof different mechanisms which may, directly or indirectly, lead toprostatic cancer growth. Desirably, the inhibition of biologicalactivity which leads to prostatic cancer growth proceeds selectively,without substantially inhibiting other desirable biological activity.Side effects of the treatment are therefore minimized.

Activation of prostatic androgen receptors stimulates growth ofprostatic cancer cells. Growth may be inhibited by blocking thesereceptors with antiandrogens as explained herein. Growth may also beinhibited by reducing the concentration of androgens available toactivate the receptors by administering at least one sex steroidsynthesis inhibitor. An inhibitor of 5α-reductase catalyzes conversionof testosterone to dihydrotestosterone (DHT). This is a particularlypreferred sex steroid synthesis inhibitor because it selectively reducesDHT levels without reducing testosterone levels. DHT stimulatesprostatic cancer growth to a much greater extent than does testosterone.Also absence of DHT forecloses fewer desirable biological functions thandoes absence of testosterone. For many patients, blocking oftestosterone production is also appropriate.

It is believed that estrogens may also increase prostatic cancer growth.Without intending to be bound by theory, estrogens appear to at least beinvolved in increasing the number of androgen receptors, and maystimulate prostatic cancer growth directly by binding estrogenreceptors. Regardless of the mechanism by which estrogens contribute toprostatic cancer growth, it has now been found that a combinationtherapy which includes inhibition of estrogen activity can enhanceeffectiveness of treatment without inhibiting desirable biologicalfunctions which, in males, are largely independent of estrogen.

There is shown in FIG. 1 a schematic representation of the site(s) ofaction of various drugs, enzymes and hormones. The followingabbreviations are used: ER: estrogen receptor; AR: androgen receptor;DHEA: dehydroepiandrosterone; Δ⁵ -diol: androst-5-ene-3β,17β-diol; Δ⁴-dione: androstenedione; DHT: dihydrotestosterone; Anti-A: antiandrogen;Anti-E: antiestrogen; ARO: aromatase; 3β-HSD: 3β-hydroxysteroiddehydrogenase, Δ⁵ -Δ⁴ isomerase; 17β-HSD: 17β-hydroxysteroiddehydrogenase; 1: antiandrogen; 2: inhibitor of 5α-reductase activity;3: inhibitor of 17α-hydroxysteroid dehydrogenase activity; 4:antiestrogen; 5: inhibitor of aromatase activity; 6: inhibitor of 3β-HSDactivity.

Referring to FIG. 1, + means increase in androgen receptor levels. Asmay be seen from FIG. 1, stimulation of the androgen receptor is shownto stimulate prostatic cancer growth, and is therefore to be prevented.In addition, stimulation of the estrogen receptor leads to increasedlevels of androgen receptors and thus may, in addition, exert directstimulatory effects on prostatic cancer growth. The action of estrogensis therefore to be prevented. Blockers of sex steroid formation fromDHEA and Δ⁴ -dione in peripheral tissues does not cause inhibition ofadrenal glucocorticoid formation. For example, cortisol and aldosteroneproduction is not inhibited and significant complications which couldresult from their inhibition are avoided. The desired inhibition of sexsteroid formation is thus aimed selectively at androgens and estrogens.

A method of inhibiting activation of the androgen receptor is treatmentwith an effective antiandrogen compound having an affinity for thereceptor site such that it binds to the receptor site and preventsandrogens from binding and activating the site. It is important toselect antiandrogens which tend to be pure antagonists and which have noagonistic activity. Otherwise, the antiandrogen which blocks thereceptor site from androgens, may itself activate the site. Preferredantiandrogens are discussed in detail below. Because it is extremelydifficult to block all receptor sites, it is desirable to simultaneouslydecrease the concentration of androgens available to activate androgenreceptors in the prostatic cancer tissue. Hence, it is desirable toinhibit secretion of androgens by the testis. This may be accomplishedby a variety of known techniques including but not limited to surgicalorchiectomy or by administering LHRH agonists or antagonists. Forexample, LHRH analogues act in a manner effective to stop the productionof bioactive luteinizing hormone, the hormone necessary to cause thetestis to produce and secrete androgens and other hormones which may beconverted to androgens in peripheral tissues. For some patients, it maybe unnecessary to inhibit testicular hormonal secretions wheresufficiently potent antiandrogens and sex steroid biosynthesisinhibitors are administered.

As may be seen from the scheme of FIG. 1, a number of hormones(especially DHEA and Δ⁴ -dione) released by the adrenals may beconverted by a variety of biological pathways into androgens andestrogens in peripheral tissues. The most potent androgen produced isDHT. It is therefore highly desirable to include an inhibitor of5β-reductase which prevents the conversion of testosterone into the morepotent androgen DHT.

In peripheral tissues, in addition to DHT, the precursors DHEA and Δ⁴-dione can be converted into the estrogens Δ⁵ -diol and estradiol. It isdesirable to have an inhibitor of 17β-hydroxysteroid dehydrogenase whichprevents the formation of testosterone as well as of Δ⁵ -diol andestradiol. In addition, since Δ⁴ -androstenedione can be converted intoestrone and then to estradiol, it may be useful to block the activity ofaromatase, the enzyme responsible for such conversion. Other sex steroidformation inhibitors, such as inhibitors of 3β-HSD can also be used.However, as mentioned earlier, when 3β-HSD is blocked in peripheraltissues, it is also likely that a similar inhibition will take place inthe adrenals, thus leading to low secretion of glucocorticoids andmineralocorticoids. When such compounds are used, essentialglucocorticoids and sometimes mineralocorticoids should be added back aspart of the therapy.

Estrogens, at physiological concentrations, are known to stimulate thegrowth of the human prostatic cancer cell line LNCaP. This effect ofestrogen may be inhibited, however, by antiestrogenic compoundsdescribed herein.

In one embodiment, the present invention provides a method of treatingprostate cancer comprising the step of administering a therapeuticallyeffective amount of an antiandrogen, and of administering atherapeutically effective amount of an inhibitor of sex steroidformation which has, as part of its molecular structure, a substitutedor unsubstituted estrogen nucleus of general structure I: ##STR3##wherein the dotted lines represent optional pi bonds; and wherein saidcompound includes as another part of its molecular structure a sidechain substitution onto a ring carbon of said general structure I in atleast one position selected from the group consisting of 7, 14, 15, 16,17 (preferably 7α, 15α, or 17α), said side chain being of the formula--R¹ [--B--R² --] L-G, as defined above, wherein general structure Ifurther includes at least one substitution selected from the groupconsisting of 15-halo, 16-halo, a 15,16 bridge atom (preferably carbon),a 14,15 bridge atom (preferably oxygen), and a 16-pi-bonded lower alkyl.

In certain embodiments, the antiandrogen utilized in the presentinvention may be represented by the general formula: ##STR4## whereinthe dotted lines represent optical double bonds; wherein R¹⁰ is hydrogenor lower alkyl, R¹³ is absent, hydrogen or methyl in β position,

R¹⁷.spsp.(α) is selected from the group consisting of hydrogen,hydroxyl, lower alkanoyloxy, lower alkyl, lower alkenyl, lower alkynyl,halo(lower)alkyl, halo(lower)alkenyl, halo(lower)alkynyl andfluro-substituted aromatic ring, and a moiety which, together withR¹⁷.spsp.(β) forms ##STR5## R¹⁷.spsp.(β) is selected from the groupconsisting of hydroxyl, (C₁ -C₂₀) alkanoyloxy, (C₃ -C₇)alkenoyloxy, (C₃-C₇) alkynoyloxy, aroyloxy, alkenoyloxy, cycloalkenyloxy,1-alkyloxy-alkyloxy, 1-alkyloxycycloalkyloxy, alkylsilyloxy, carboxyl,alkanoyl and a moiety which together with R¹⁷.spsp.(α) forms ##STR6##

Antiandrogens useful in the combination therapy of the invention alsoinclude but are not limited to flutamide (available from Schering-PloughCorp., Kenilworth, N.J., under trade name EULEXIN), Nilutamide(available from Roussel of Paris, France, under trade name ANANDRON),cyproterone acetate (available from Schering AG, Berlin under trade nameANDROCUR), Casodex available from ICI Pharmaceuticals, Macclesfield,England. Preferably, the antiandrogen has, as part of its molecularstructure, a substituted or unsubstituted androgenic nucleus, and asanother part of its molecular structure, the side-chain --R'[--B--R²--]_(x) L-G as defined above. Numerous syntheses of the preferredcompounds set forth in the U.S. patent application of Labrie and Merandentitled "Androgen Derivatives for use in the inhibition of sex steroidactivity" which is being executed on even date herewith, the entiredisclosure of which is hereby incorporated by reference as though fullyset forth herein. A preferred antiandrogen is ##STR7## which may besynthesized as set forth below.

EXAMPLE 1 Synthesis of N-butyl,N-methyl-11-(17'β-hydroxy-4'-androsten-3'-on-7'β-yl) undecanamide (EM101) (5, ×=10) (Scheme 1)

17β-acetoxy-7α-(11'-hydroxy undecanyl)-4-androsten-3-one (2)

Under argon atmosphere, in a flame dried apparatus with magneticstirrer, a solution of 11-bromo undecanol tetrahydropyranyl ether (25 g,74 mmol) in anhydrous THF (150 ml) was added dropwise toiodine-activated magnesium (1.9 g). The mixture was kept at roomtemperature overnight and then was cooled to -30° C. and anhydrouscuprous chloride (0.3 g) was added quickly. After 45 min of stirring atthis temperature, commercial 4,6-androstadien-17β-ol-3-one acetate (1)(10 g, 30.5 mmol) in anhydrous THF (100 ml) was added dropwise during 4h. After 35 min, acetic acid (6 ml) and water (100 ml) was added. Themixture was allowed to reach room temperature and was stirred overnight.Afterwards, the organic compound was extracted with ether (3X). Theorganic layers were washed with water, dried on magnesium sulfate andevaporated. The residue was dissolved in acetic acid (35 ml) and water(100 ml) and kept 48 h at room temperature. And then, the organiccompounds were extracted with ether (3X). The organic layers were washedwith saturated sodium bicarbonate solution and water, dried on magnesiumsulfate and evaporated. The product was purified by Silica gel drycolumn chromatography (Kieselgel, 60F254, Merk, 0.063-0.200 mm, 150 g).Elution with a mixture of methylene chloride and ethyl acetate (20:1v/v) gave 17β-acetoxy-7α-(11'-hydroxy-undecanyl)-4-androsten-3-one (2a,1.46 g, 2.8 mmol, 9.2%) as a colorless oil; IR ν_(max) neat 3450, 1740,1685, 1620 and 1245 cm⁻¹ ; NMR 0.84 (s, 3H, 18'--CH₃), 1.21 (s, 3H,19'--CH₃) 2.05 (s,3H, OCOCH₃), 3.61 (t, 2H, J=6.59 Hz, H-C.1'), 4.61 (t,1H, J=7.69 Hz, H-C.17) and 5.73 (s, 1H, H-C.4) and17β-acetoxy-7β-(11'-hydroxy undecanyl)-4-androsten-3-one (2b, 0.9 g, 1.7mmol, 5.6%) as a colorless oil.

11-(17'β-acetoxy-4'-androsten-3'-androsten-3'-on-7'α-yl) undecanoic acid(3)

To 17β-acetoxy-7α-(11'-hydroxy undecanyl)-4-androsten-3-one (2a, 800 mg,1.6 mmol) dissolved in acetone (50 ml) and cooled to 0° C. was addedunder stirring during 5 min, a solution of Jones' reagent (8N chromicacid solution) (0.283 ml). After 15 min, isopropanol (0.5 ml) was addedfollowed by water and the mixture was extracted with ethyl acetate (3X).The organic layers were washed with brine, dried on magnesium sulfateand evaporated to dryness under reduced pressure. The crude11-(17'β-acetoxy-4'-androsten-3'-on-7'α-yl) undecanoic acid (3) (740 mg)was used in the next step without purification.

N-butyl, N-methyl-11-(17'β-acetoxy-4'-androsten-3'-on-7'α-yl)undecanamide (4)

To a solution of the above undecanoic acid derivative 3 (390 mg, 0.78mmol) in anhydrous methylene chloride (8 ml) cooled at -10° C. wasadded, under stirring, triisobutylamine (240 μl) andisobutylchloroformate (140 μl). After 30 min, N-methylbutylamine (1.8 mlwas was added and the mixture was stirred at room temperature for 1 h.Methylene chloride was added. The organic solution was washed with 1Nhydrochloric acid, water, saturated sodium bicarbonate solution andfinally with water, dried on magnesium sulfate and evaporated todryness. The residue was chromatographed on silica gel (Kieselgel,60F254, Merck, 0.063-0.200 mm, 20 g). Elution with a mixture of diethylether and methylene chloride (1:20, v/v) gave N-butyl,N-methyl-11-(17'β-acetoxy-4'-androsten-3'-on-7'α-yl) undecanamide 4 (230mg, 0.39 mmol, 46% for the alcohol (2a)) as a colorless oil; IR ν_(max)neat 1740, 1680, 1640 and 1240 cm⁻¹ ; NMR 0.84 (s, 3H, 18'--CH₃), 0.95(t, 3H, J=6.93 Hz, N--(CH₂)₃ CH₃), 1.21 (s, 3H, 19'--CH₃), 2.04 (s, 3H,OCOCH₃), 2.91 and 2.97 (2s, 3H, N--CH₃), 3.26 and 3.36 (2t, 2H, J=7.86Hz, N--CH₂ C₃ H.sub. 7), 4.61 (t, 1H, J=8.42 Hz, H--C.17') and 5.72 (s,1H, H--C.4').

N-butyl, N-methyl-11-(17'β-hydroxy-4'-androsten-3'-on-7'α-yl)undecanamide (5) (EM 101)

The above acetoxy amide 4 (170 mg, 0.29 mmol) was dissolved in methanol(20 ml) and 6% potassium carbonate (2 ml) and heated at 65° C. for 200min. After cooling, acetic acid (1 ml) and water (150 ml) were added andthe mixture was extracted with ethyl acetate (3×). The organic layerswere washed with water, dried on magnesium sulfate and evaporated todryness. The residue was purified by Silica gel dry columnchromatography (Kieselgel, 60F254, Merk, 0.063-0.200 mm, 20 g). Elutionwith a mixture of diethyl ether and methylene chloride (1:9, v/v) gaveN-butyl-N-methyl-11-(17'β-hydroxy-4'-androsten-3'-on-7'α-yl)undecanamide (EM 101, 94 mg, 0.17 mmol, 58%) as a colorless oil; IRν_(max) (neat) 3400, 1670 and 1640 cm⁻¹ ; NMR 0.80 (s, 3H, 18'--CH₃),0.95 (t,3H, J=6.75 Hz, N--(CH₂)₃ CH₃), 1.21 (s, 3H, 19'--CH₃), 2.91 and2.97 (2s, 3H, N--CH₃), 3.25 and 3.35 (2t, 2H, J=7.3 Hz, N--CH₂ C₃ H₇),3.67 (t, 1H, J=8.18, H--C.17') and 5.72 (s, 1H, H--C.4'). ##STR8##

Sex steroid formation inhibitors useful in the combination therapy ofthe invention include but are not limited to inhibitors of 5α-reductaseactivity, inhibitors of 17β-hydroxysteroid dehydrogenase activity,inhibitors of 3β-hydroxysteriod dehydrogenase activity and inhibitors ofaromatase activity.

A typically suitable 5α-reductase inhibitor is MK-906, a product ofMerck, Sharp & Dohme (Mc Connell et al., J. Urol. 141: 239A, 1989).Another inhibitor of 5α-reductase is17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (4-MA)(Brooks et al., Endocrinology 109: 830, 1981; Liang et al.,Endocrinology 112: 1460, 1983). Other 4-azasteroids acting as5α-reductase inhibitors can be formed in Liang et al., J. Biol. chem.259: 734-739, 1984; and in Brooks et al., Steroids 47: 1-19, 1986,6-methylene-4-pregnene-3,20-dione has also been described as5α-reductase inhibitor (Petrow et al., J. Endocrinol. 95: 311-313,1982). Similar properties have been described for4-methyl-3-oxo-4-aza-5α-pregnane-30(s) carboxylate (Kadohama et al., J.Natl. Cancer Inst. 74: 475-486, 1985).

Trilostane and epostane have been described as inhibitors of3β-hydroxysteroid dehydrogenase activity (Ernshaw et al., Clin.Endocrinol. 21, 13-21, 1984; Robinson et al., J. Steroid Biochem. 21,601-605, 1984; Lambert et al., Ann. Clin. Biochem. 23, 225-229, 1986;Potts et al., Steroids 32, 257-267, 1978) and have been successfullyused for the treatment of breast cancer in combination withcorticosteroids (Beardwell et al., Cancer Chemother. Pharmacol. 10:158-160, 1983; Williams et al., Cancer Treat. Rep. 71, 1197-1201, 1987).

4-MA, (17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one) hasbeen found to inhibit 3β-hydroxysteroid dehydrogenase activity ingranulosa cells (Chan et al., Biochem. Biophys. Res. Commun. 144,166-171, 1987). Epostane has been shown to inhibit 3β-hydroxysteroiddehydrogenase activity in pregnant goats (Taylor, J. Endocrinol. 113,489-493, 1987).

Preferred inhibitors of 17β-hydroxysteroid dehydrogenase activityinclude but are not limited to:

N-butyl, N-methyl-11-(16'α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl) undecanamide ("EM 139"). ##STR9##

N-n-butyl-N-methyl-11-(16'α-chloro-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 170") ##STR10##

N-n-butyl-N-methyl-11-(16'α-bromo-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 171") ##STR11##

Examples of certain synthesis schemes for EM 139, EM 170 and EM 171 areset forth below (see example 2 and schemes 2 and 3). Those of skill inthe art will recognize analogous schemes for synthesizing analogouscompounds.

EXAMPLE 2 Synthesis of Preferred Sex Steroid Activity InhibitorsSynthesis of a starting compound, N-n-butyl,N-methyl-11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanamide (14a) (SCHEME 2)

19-nor-testosterone acetate 3-enolacetate (7)

In an apparatus supplied with a drierite drying tube, a solution of19-nor-testosterone (6) (100 g; 0.365 mole) in acetic anhydride (200ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at refluxunder magnetic stirring, for 3 h and then concentrated to dryness undervacuum. The dry residue was triturated in absolute ethanol, filtered andwashed with little portions of absolute ethanol. After drying,19-nor-testosterone acetate 3-enolacetate was obtained as a white powder(121.4 g, yield 93%) mp. 176°-177° C. The structure was confirmed byspectroscopic means.

17β-acetoxy-estra-4,6-dien-3-one (8)

To a cooled suspension of enolacetate (121 g; 0.337 mole) in a mixtureof DMF (330 ml) and water (7.2 ml) at 0° C. was added, under nitrogen,over a period of 1 h, N-bromosuccinimide (63 g). The resulting solutionwas stirred for an additional 0.5 h at 0° C. Then lithium carbonate(60.8 g) and lithium bromide (30.4 g) were added. The mixture was heatedat 95° C. for 3 h and then poured into 1.7 of ice-cold water containing165 ml of glacial acetic acid. After stirring during 15 hours, the crude17β-acetoxy-estra-4,6-dien-3-one (8) was filtered, washed with water,dried in a desiccating apparatus and recrystallized twice from isopropylether (72 g, yield 68%, mp 110° C.). The structure was confirmed byspectroscopic means.

7α-(11'-acetoxy-undecyl) 17β-acetoxy estra-4-en-3-one (9)

A. Preparation of reagents and solvents

11-bromo undecanol tetrahydro pyranyl ether

11-bromo-undecanol (100 g, 398 mmol) was dissolved in dry ether (768 ml)and the solution was cooled to 0° C. using an ice/H₂ O bath. To thissolution was added HCl gas (2.13 g, 58.4 mmol, 26 ml of HCl/ether).

To this mixture, a solution of 3,4-dihydro-2H-pyran (39.9 g, 43.3 ml)freshly distilled in dry ether (218 ml) was added over a period of 90min. The solution was then stirred over a period of 16 hours at roomtemperature. Afterwards, sodium bicarbonate was added to the mixture.The residue was filtered and the solvent was evaporated under vacuum.

The product was then filtered through basic alumina (250 g, Woelm, gradeII) using petroleum ether (30-60) as solvent (112 g, 81%).

B. Grignard reagent

In a dry three-neck flask (1000 ml) under dry argon, magnesium (12.0 g,494 mmol) was placed and activated with iodine. Magnesium was heatedwith the flame to remove iodine and to dry the apparatus. The system wasthen cooled to -20° C., and a solution of 11-bromo-undecanol tetrahydropyranyl ether (73.8 g, 211 mmol) in dry THF (420 ml) was added dropwise.The mixture was stirred under dry argon during one day at -20° C.

The mixture was cooled to -35° C. (±2° C.) using a dry ice/CCL₄ /acetonebath. The anhydrous cuprous chloride (1.18 g, 12 mmol) was added and themixture was stirred over a period of 0.5 h.

C. Addition of Grignard reagent

After 0.5 h, using the same apparatus mentioned above (Ar, -35° C.), asolution of 17 β-acetoxy estra-4,6-diene-3-one (8) (32.0 g, 102 mmol) indry THF (300 ml) was added dropwise over a period of 6 h to the Grignardreagent (red coloration appeared and disappeared). The mixture wasstirred for an additional 1 h and, after removal the cooling bath,acidified (about 0° C.) with acetic acid (40 ml), diluted with water andextracted with ether (3×). The ether solution was washed with a saturatesodium bicarbonate solution and water. The organic layer was dried overanhydrous magnesium sulfate and evaporated under reduced pressure todryness.

The residue was dissolved in MeOH (660 ml) and 5N HCl (180 ml), refluxedfor 1 h and 45 min, then concentrated under reduced pressure and cooledin an ice bath. The mixture was then filtered to remove the whiteprecipitate. After the solution had been diluted with water andextracted with methylene chloride (3×), the organic layer was dried overanhydrous MgSO₄ and evaporated under reduced pressure to dryness.Finally, the product (55.9 g, brown oil) was chromatographed on silicagel (Kieselgel 60F254, Merck, 0.063-0.200 mm, 1500 g). Elution withmixtures of methylene chloride and ethyl acetate (4:1 to 1:2 v/v) andthen pure ethyl acetate gave crude 7α-(11'-hydroxy-undecyl)-17β-hydroxyestra-4-en-3-one (34.8 g) which was dissolved in dry pyridine (200 ml)and dry acetic anhydride (200 ml), stirred 17 h at room temperature andthen poured in ice-water. The product was extracted with methylenechloride (3× ), washed with 1N hydrochloric acid, water, saturatedsodium bicarbonate and water (3×), dried on anhydrous magnesium sulfateand filtered. After evaporation of solvent, the mixture (35 g) of 7α-and 7β-diacetoxyenones and degradation products of Grignard reagent wereseparated by flash chromatography on silica gel (Kieselgel 60, Merck,230 mesh ASTM, 2.0 ) developed with a mixture of hexane and diethylether (2:3 v/v). The first product eluted was pure amorphous7α-(11'-acetoxy undecyl) 17β-acetoxy-estra-4-en-3-one, (9) (20.8 g, 39.4mmol, yield from dienone was 39.0%). Further elution gave the 7β-isomer(10) (5.4 g, 10.3 mmol, 10%). All structures were determined byspectroscopic means.

7α-(11'-hydroxy-undecyl) estra-1,3,5(10)-trien-3,17β-diol (11a)

Under dry argon, a solution of 7α-(11'-acetoxy undecyl)17β-acetoxy-estra-4-en-3-one (9) (17.0 g, 32.4 mmol) in dry acetonitrile(150 ml) was added rapidly to a suspension of cupric bromide (14.8 g,66.2 mmol) and mmol) and lithium bromide (2.89 g, 33.6 mmol) in warmacetonitrile (75 ml). The mixture was heated to reflux over a period of30 min and stirred vigorously, and then cooled to room temperature. Asaturated aqueous solution of sodium bicarbonate (50 ml) was added, andthen the organic compound was extracted with ethyl acetate (3×150 ml).The organic layers were washed with water, dried over anhydrousmagnesium sulfate, filtered and evaporated under vacuum to dryness. Theresidue was chromatographed on silica gel (Kieselgel 60F254 Merck0.063-0.200 mm; 1000 g). Elution with hexane-ethyl acetate (1:1 v/v)gave the 7α-(11'-acetoxy-undecyl) estra-1',3',5'(10')-trien-3,17β-diol,17β-acetate (11b) (8.51 g; 50.3%) and the starting product (1.33 g;15%).

The above diacetate phenol (8.51 g, 16.2 mmol) was dissolved in methanol(90 ml) and sodium hydroxyde 30% (w/v) (9 ml). The mixture was refluxedfor 90 min under dry nitrogen. The solution was then concentrated undervacuum and diluted with hydrochloric acid (10% v/v). The mixture wasextracted using ethyl acetate (4×150 ml) and the ethyl acetate extractwas washed with water, dried over anhydrous magnesium sulfate, filteredand evaporated under vacuum. The evaporation gave 7β-(11'-hydroxyundecyl) estra-1,3,5(10)-trien-3,17β-diol (11a) (6.99 g, 98% brut) as ayellow foam, the structure of which was confirmed by spectroscopicmeans.

3-benzoyloxy 7α-(11'-hydroxy undecyl) estra-1,3,5(10)-trien-17β-ol (12)

The above triol (6.99 g; 15.8 mmol) was dissolved in acetone (25 ml) andan aqueous solution of sodium hydroxyde (1N, 19.1 ml). The mixture wascooled to 0° C. using an ice/water bath. Benzoyl chloride (2.22 ml, 19.1mmol) was then added dropwise. The mixture was stirred for 40 min at 0°C. and then diluted with water. The solution was extracted using ethylacetate (3X) and the organic layers were washed with a saturated aqueoussolution of sodium bicarbonate and finally with water. The ethyl acetatesolution was dried over anhydrous magnesium sulfate, filtered andevaporated under vacuum to dryness. Then, the residue was immediatelychromatographed on silica gel (Kieselgel, 60F254, 0.063-0.200 mm; 500g). The chromatography was carried out, first, using methylene chlorideas solvent (about 1 liter) and secondly the pure 3-benzoyloxy7α-(11'-hydroxy undecyl) estra-1,3,5(10)-trien-17β-ol (12), colorlessoil (6.50 g, 75%) was eluted with methylene chloride-ethyl acetate (5:1about 1 liter and 4:1; v/v). The structure was confirmed byspectroscopic means.

11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl) undecanoicacid (13)

To a cooled solution of 3-benzoyloxy-7α-(11'-hydroxyundecyl)estra-1,3,5(10)-trien-17β-ol (12) (4.3 g) in acetone (100 ml)was added dropwise Jone's reagent (8N-chromic acid solution, 6.7 ml).After 30 min, isopropanol (40 ml) was added and the mixture wasconcentrated under vacuo. Water was added and the mixture was extractedfour times with ethyl acetate. The organic layers were washed twice withbrine, dried over magnesium sulfate and evaporated to dryness. The crude11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl) undecanoicacid (13) (3.94 g) was used in the next step without purification.##STR12##

N-n-butyl,n-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanamide (14b)

To 11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanoic acid (13) (3.94 g, 7.22 mmol), dissolved in anhydrous CH₂ Cl₂(100 ml) and cooled at -10° C. was added tributylamine (2.18 ml, 9.15mmol) and isobutylchloroformate (1.30 ml, 10.0 mmol). The solution wasstirred during 35 min. and N-methylbutylamine (13 ml, 109.7 mmol) wasadded. The mixture was warmed to room temperature and stirred during 1h. Afterward, CH₂ Cl₂ was added and the organic phase was washed with 1NHCl water, saturated sodium bicarbonate solution and finally with water,dried with anhydrous MgSO₄ and the solvent was removed under reducedpressure. The residue was purified by chromatography on silica gel.Elution with mixture of EtOAc/hexane (1.5:8.5 v/v) yielded N-butyl,N-methyl-11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanamide (14a) (4.25 g, 96%) as colorless oil; IR ν(neat) 1750, 1725and 1640 cm⁻¹. The above described benzoyloxy amide (341 mg, 0.54 mmol)was dissolved in methanol (10 ml) and cooled at 0° C. Following this 2NNaOH (5 ml) was added and the mixture was stirred during 60 min. at 0°C. The solution was neutralized with 1N HCl and extracted with CH₂ Cl₂.The organic phase was dried with anhydrous MgSO₄ and the solvent wasremoved under reduced pressure. The residue was purified bychromatography on silica gel. Elution with mixture of EtOAc/hexane (3:7v/v) yielded N-butyl, N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',4'(10')-trien-7'α-yl) undecanamide (14b) (284 mg, 97%) as colorless oil;¹ H-NMR δ(CDCl₃) 0.91 (s,3H,18'--CH₃), 2.76 app(d,1HJ=16,3 Hz, part ofABX system, 6'-H) 2.96 and 2.98 (2s,3H N--CH₃), 3.27 and 3.38(2t_(app),2H,J=7.5 Hz,N--CH₂ --), 6.63 (broad s,1H,4'-H), 6.70 (broadd,1H,J=8.5 Hz, 2'-H), 7.12 (d,1H,J=8.4 Hz,1'-H); IR ν_(max) (neat) 3270,1730, 1615 cm⁻¹ ; MS m/e 523 (M⁺,100%), 508 (M⁺ --CH₃,32%), 142 (C₂ H₄CON(CH₃)C₄ H₉ ⁺, 47%).

16-Halo-Estradiol Undecanamide (Scheme 3)

N-n-butyl,N-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10'),16'-tetraen-7'α-yl)undecanamide (15)

The ketone amide 14 b (163 mg, 0.50 mmol) was dissolved in isoprenylacetate (10 ml). p-toluenesulfonic acid (44 mg) was then added and thesolution was distilled to about two-thirds of the original volume in 7 hand was then stirred at reflux for 12 h. Afterwards, the solution wascooled with an ice-water bath and extracted with 50 ml of cooled ether.The ether was washed with a cooled satured sodium bicarbonate and water.The organic phase was dried with anhydrous MgSO₄ and the solvent wasremoved under reduced pressure. The residue was filtered through alumina(15 mm×50 mm alumina Woehlm neutral, activity II) using a mixture ofbenzene-diethyl ether (3:7 v/v) as eluant. The solvent was removed underreduced pressure and, the residue was purified by flash chromatographyon silica gel. Elution with mixture of EtOAc/hexane (1:4 v/v) yieldedthe N-butyl, N-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10'),16'-tetraen-7'α-yl) undecanamide (15) (244 mg, 80%) as colorless oil; ¹H-NMR δ_(m) (CDCl₃) 0.92 (s,3H,18'-CH₃), 0.92 and 0.95 (2t,3H,J=7.0Hz,N(CH₂)₃ CH₃), 2.18 (s,3H,17'-OCOCH₃), 2.28(s,3H,3'OCOCH₃), 2.76 app(d,1H,J=16.1 Hz, part of ABX system,6'-H), 2.90 and 2.96 (2s,3H,N-CH₃),3.26 and 3.35 (2t_(app),2H,J=7.6 Hz,N-CH₂ -), 5.52 (m,1H,16'-H), 6.80(broad s,1H,4'-H), 6.85 (dd,1H,J₁ =9.1 Hz and J₂ =3.0 Hz,2'-H), 7.27(d,1H,J=9.1 Hz,1'-H); IRν_(max) (neat) 1750, 1635, 1200 cm-¹ ; MS m/e607 (M⁺,2 %), 5(M⁺ --COCH₂,100%), 550 (M⁺ --COCH₂ --CH₃,13%), 523 (M⁺--2COCH₂,45%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,55%), 129 (C₄ H₉ (CH₃)NCOCH₃⁺,38%), 114 (C₄ H₉ (CH₃)NCO⁺, 60%), 86 (C₄ H₉ (CH₃)N⁺, 25%); EXACT MASScalcd for C₃₈ H₅₇ O₅ N 607.4239, found 607.4234.

N-butyl,N-methyl-11-(16'α-chloro-3'acetoxy-17'-oxo-estra-1',3',4'(10')-trien-7'α-yl)undecanamide (16, X═Cl)

To diacetate amide 15, dissolved in 5 ml of acetone, was added asolution of sodium acetate (2.6 equivalents) in acetic acid and water(1:11.3 v/v) and then, was treated with tertbutyl hypochlorite (1 eq.)prepared from t-butanol (4 ml) and Javel water (Javex 6.1%, 50 ml). Theclear solution was warmed to 55° C. and stirred for 1 h. Afterwards, thesolvent was evaporated to dryness. The residue was dissolved in ether(100 ml) and water was added (20 ml). The organic phase was washed withwater, dried with anhydrous MgSO₄ and evaporated to dryness. The residuewas purified by chromatography on silica gel carried out with mixture ofEtOAc/hexane (3:7 v/v) to give the N-butyl,N-methyl-11-(16'α-chloro-3'-acetoxy-17'-oxo-estra-1',3',4'(10')-trien-7'α-yl)undecanamide 16, X═Cl) (115 mg, 89%) as colorless oil; ¹ H-NMR ν (CDCl₃)0.92 and 0.95 (2t,3H,J=7.0 Hz,N(CH₂)₃ CH₃), 0.96 (s,3H,18'--CH₃), 2.28(s,3H,3'--OCOCH₃), 2.80 app (d,1H,J=16,6 Hz, part of ABX system, 6'-H)2.90 and 2.96 (2s,3H, N--CH₃), 3.24 and 3.35 (2t_(app),2H,J=7.4 Hz,--N--CH₂ --), 4.46 (d,1H,J=6.6 Hz,16'β-H), 6.82 (broad s,1H, 4'-H), 6.86(dd,1H,J=9.1 Hz and J₂ =,2.6 Hz,2'-H), 7.29 (d,1H,J=9.1 Hz,1'-H); IRν_(max) (neat) 1750, 1640, 1205 cm⁻¹ ; MS m/e 601, 599 (M⁺,24%, 68%),142 (C₂ H₄ CON(CH₃)C₄ H.sub. 9⁺, 100%), 114 (C₄ H₉ (CH₃)NCO⁺,93%).

N-butyl,N-methyl-11-(16α-chloro-3',17'-dihdroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 139") and ("EM 170")

A stirred solution of haloketone amide (16, X═Cl) in anhydroustetrahydrofuran (THF) (10 ml) under argon was chilled to -70° C. with2-propanol/dry ice bath. A solution of 1.0M of lithium aluminium hybride(2 eq.) was then added dropwise. After 30 min, the reaction was allowedto return slowly at 0° C. for 5 min, then was quenched by the dropwiseaddition of a mixture of THF-EtOAc (5 ml) (1:1 v/v) and acidified atpH˜4 with (10%) HCl. The mixture was stirring for 5 min at roomtemperature and then extracted with EtOAc. The organic phase was washedwith water, dried on anhydrous Na₂ SO₄ and evaporated under reducedpressure. The residue was chromatographed on silica gel with a mixtureof EtoOAc/hexane (4:6 v/v) as eluant:

N-butyl,N-methyl-11-(16'α-chloro-3'17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 170")

(15 mg, 29%) as colorless oil; analytical sample was obtained by HPLCpurification; ¹ H-NMR δ(CDCl₃, 400 MHz) 0.79 (s,3H,18'--CH₃), 0.93 and0.96 (2t, 3H,J=7.3 Hz,N(CH₂)₃ CH₃), 2.80 (2H,J₆,6 =17.1 Hz and J₆,7 =4.5Hz, Δδ=24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2s, 3H,N--CH₃), 3.26(dd,J₁ =7.6 Hz and J₂ =7.4 Hz) and 3.32-3.43 (m)--[2H,--N--CH₂ --], 3.71(d,1H,J=4.5 Hz,17'β-H), 4.63 (ddd, 1H, J₁₆,15 =10.2 Hz, J₁₆,17 =4.5 Hzand J₁₆,15 3.9 Hz, 16'β-H), 6.50 (d, 1H, j=24 Hz, 3' -OH), 6.60 (d,1H,J=2.5 Hz, 4'-H), 6.66 (dd,1H,J₁ =8.4 Hz and J₂ =2.5 Hz, 2'-H), 7.14(d,1H,J=8.5 Hz, 1'-H); IR ν_(max) (neat) 3300, 1615, 1495 cm⁻¹ ; MS m/e561,559 (M⁺, 40%, 100%), 523 (M⁺ -HCl, 20%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,44%), 114 (C₄ H₉ (CH₃)CNO⁺, 37%); Exact mass calculated for C₃₄ H₅₄ O₃N³⁵ Cl 559.3785, found 559.3821; and

-N-butyl,N-methyl-11-(16'α-chloro-3',17'β-dihydroxy-estra-1'3',5'(10')-trien-7'α-yl)undecanamide ("EM 139")

(25 mg, 55%) as a colorless oil; analytical sample was obtained by HPLCpurification; 1H-NMR δ(CDCl₃, 400 MHz), 0.81 (s,3H, 18'---CH₃), 0.93 and0.96 (2t, 3H,J=7.3 Hz, (CH₂)₃ CH₃), 2.78 (2H, J₆,6 =16.2 Hz and J₆,7=4.5 Hz, Δ⁵ =24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2s, 3H,N-CH₃),3.27 (dd, J₁ =7.6 Hz and J₂ =7.5 Hz) and 3.31-3.45 (M)[2H, --N--CH₂ --],3.86 (dd, 1H, J₁₇,17 -_(OH) =3.4 Hz and J₁₇,16 =5.9 Hz, 17'α-H), 4.11(ddd, 1H, J₁₆,15 =10.8 Hz, J₁₆,17 =5.9 Hz and 4.11 (ddd, 1H, J.sub.16,15 =10.8 Hz, J₁₆,17 =5.9 Hz and J₁₆,15 =2.5 Hz, 16'β-H), 6.56 (d, 1H,J=19.7 Hz, 3'--OH), 6.61 (d, 1H, J=2.5 Hz, 4'-H), 6.66 (dd, 1H, J₁ =8.4Hz and J₂ =2.6 Hz, 2'-H), 7.13 (d, 1H, J=8.4 Hz, 1'-H); IR ν_(max)(neat) 3320, 1615, 1490 cm⁻¹ ; MS m/e 561,559 (M⁺, 38%, 100%), 523 (M⁺-HCl, 16%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺, 80%), 114 (C₄ H₉ (CH₃)NCO⁺,76%);exact mass calculated for C₃₄ H₅₄ O₃ N³⁵ Cl 559.3785, found 559.3825.##STR13##

N-n-butyl,N-methyl-11-(16'α-bromo-3'-acetoxy-17'-oxo-estra-1',3',5'-(10'),trien-7'α-yl)undecanamide (16, X═Br)

To the above diacetate 15 (244 mg, 0.40 mmol) dissolved in 10 ml ofacetic acid was added dropwise with stirring within 10 minutes and atroom temperature, a brominating solution composed of 50 mg (0.6 mmol) ofsodium acetate, 1.6 ml of acetic acid, 0.04 ml of water and 63.9 mg(0.02 ml, 0.40 mmol) of bromine. During the course of this reaction, ared coloration appeared and disappeared. To the solution, 50 ml of etherwas added and the organic phase was washed with water (4×50 ml) followedby a saturated sodium bicarbonate solution (2×50 ml) and finally withwater (3×50 ml). The combined phase was dried over anhydrous magnesiumsulfate and the solvent was removed in vacuo. The residue waschromatographed on silica gel (Kieselgel, 60F254, Merck, 0.063-0.200mm). Elution with a mixture of hexane-ethyl acetate (4:1 v/v) yieldedN-butyl, N-methyl-11-(16α-bromo-3'-acetoxy-17'-oxo-estra-1',3',5'(10'),trien-7'-α-yl) undecanamide (16, X═Br) (201 mg, 78%) ascolorless oil (201 mg, 78%), as colorless oil; ¹ H-NMR o (CDCl₃), 0.94(s, 3H,18'--CH₃), 2.28 (s, 3H, 3'--OCOCH₃), 2.82 app (d,1H,J=16.4 Hz,part of ABX system, 6'-H), 2.90 and 2.96 (2s, 3H,N--CH₃), 3.24 and 3.35(2t_(app), 2H, J=7.7 Hz, --N--CH₂ --), 4.58 (t,1H,J=3.6 Hz, 16β-H), 6.82(broad s,1H,4'-H), 6.88 (dd,1H, J=8.0 Hz and J₂ =4.0 Hz,2'-H), 7.29(d,1H,J=8.0 Hz, 1'-H); MS m/e 644 (M⁺,7 %), 565 (M⁺ --Br, 77%), 522 (M⁺--Br--COCH₂, 55%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺, 67%), 114 (C₄ H₉(CH₃)NCO⁺, 66%), 88 (100%).

N-butyl,N-methyl-11-(16'α-bromo-3',17'-dihydroxy-estra-1',3,4'(10')-trien-7'α-yl)undecanamide ("EM 105") and ("EM 171")

A solution of bromoketone amide 16 (X═Br) (295 mg, 0.46 mmol) inanhydrous tetrahydrofuran (10 ml) under argon was chilled to -70° C. anda solution of 1.0M of lithium aluminium hybride in ether (0.92 ml, 0.92mmol) was added dropwise with rapid magnetic stirring. After 30 min, thereaction was quenched by the dropwise addition of a mixture of THF-ethylacetate (1:1 v/v) and acidified by 10% hydrochloric acid. The mixturewas stirring for 5 min at room temperature and then extracted with ethylacetate. The organic phase was washed with water, dried on anhydroussodium sulfate and evaporated to dryness under reduced pressure. Theresidue was purified by chromatography on silica gel. Elution with amixture of hexane-ethyl acetate (7:3 v/v) gave:

N-n-butyl,N-methyl-11-(16'α-bromo-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 171")

(63 mg, 21%) as colorless oil; ¹ H-NMR δ(CDCl₃, 400 MHz) 0.81 (s, 3H,18'--CH₃), 0.93 and 0.96 (2t, 3H,J=7.3 Hz,N(CH₂)₃ CH₃), 2.79 (2H,J₆,6=16.6 Hz, J₆,7 =4.7 Hz, =Δδ=24.34 Hz, system ABX, 6'-H), 2.94 and 2.99(2s,3H,N--CH₃), 3.27 (dd,2H,J₁ =7.7 Hz and J₂ =7.5 Hz, --N--CH₂ --),3.31-3.44 (m,2H,--N--CH₂ --), 3.66 (dd,1H,J₁₇,17 =1.4 Hz, J₁₇,16 =4,3Hz, 17'β-H), 4.68 (dt,1H,J₁₆,17 =4,3 Hz, m, J₁₆,15 =9.7 Hz, 16'β-H),6.60 (d,1H,J=2.4 Hz, 4'-H), 6.65 (dd, 1H,J=8.5 Hz and J₂ 2.5 Hz, 2'-H),7.14 (d,1H,J=8.5 Hz, 1'-H); IR ν_(max) (neat) 3300, 1615, 1495 cm⁻¹ ; MSm/e 605,603 (M⁺, 17%), 523 (M⁺ -HBr, 81%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,100%), 114 (C₄ H₉ (CH₃)NCO⁺, 97%); Exact mass calculated for C₃₄ H₅₄ O₃N⁷⁹ Br 603.8289, found 603.3304. N-n-butyl,N-methyl-11-(16'α-bromo-3',17'β-dihydroxy-estra-1',3',-5'(10')-trien-7α-yl)undecanamide ("EM 105")

(170 mg, 50%) as a colorless oil; analytical sample was obtained by HPLCpurification; ¹ H-NMR δ(CDCl₃, 400 MHz), 0.80 (s,3H,18,--CH₃), 0.93 and0.96 (2 t,3H,J=7.3 Hz,N(CH₂)₃ CH₃), 2.80 (2H,J₆,6 =16.4,J₆,7 =4.6 Hz,Δδ=24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2s,3H,N--CH₃), 3.27 (dd,2H,J₁ =7.7 Hz and J₂ =7.5 Hz, --N--CH₂ --), 3.31-3.45 (m,2H,--N--CH₂--), 4.02 (dd,1H,J₁₇,17 =3.7 Hz, and J₁₇,16 =6.1 Hz, 17'α-H), 4.15(ddd,1H,J₁₆,15 =10.2 Hz, J₁₆,17 =6.1 Hz and J₁₆,15 =2.9 Hz, 16'β-H),6.61 (d, 1H,J=2.5 Hz, 4'-H), 6.66 (dd,1H,J=8.4 Hz and J₂ 2.5 Hz, 2'-H),7.12 (d,1H,J=8.4 Hz, 1'-H); IR ν_(max) (neat) 3320, 1610, 1490 cm⁻¹ ; MSm/e 605, 603 (M⁺, 29%), 523 (M⁺ -HBr, 100%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,70%), 114 (C₄ H₉ (CH₃)NCO⁺, 60%); Exact mass calculated for C₃₄ H₅₄ O₃N⁷⁹ Br 603.3289, found 603.3289.

Antiestrogens useful in the combination therapy of the invention includebut are not limited to Tamoxifen, commercially available from ImperialChemical Industries, and EM 139, EM 170 and EM 171 whose synthesis areset forth above. Some steroidal antagonists also function as inhibitorsof sex steroid formation. The antiestrogens EM 139, EM 170 and EM 171,for example, exhibit the dual function of acting as sex steroidformation inhibitors. For this reason, a combination therapy requiringboth an inhibitor of sex steroid formation and a steroidal antagonistmay be produced by administering a single active compound (alone ortogether with diluent) capable of performing both functions. Anotherexample of a dual function active ingredient is the antiandrogen EM 101which has also shown an inhibitory effect on sex steroid formation.

The inhibitor of sex steroid biosynthesis is preferably capable ofacting at least in peripheral tissue (extra-testicular andextra-adrenal). In preferred embodiments, it is used in association withan antiandrogen, and with an LHRH agonist or LHRH antagonist. The use ofan LHRH agonist is the more preferred method of chemical castration.Surgical castration may alternatively be used as a means of inhibitingtesticular hormonal secretions, but chemical castration is preferred.

By the term "LHRH agonist" is meant synthetic analogues of the naturalluteinizing hormone-releasing hormone (LHRH), a decapeptide of thestructure:L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-arginyl-L-prolylglycyl-NH₂.

Typical suitable LHRH agonists include nonapeptides and decapeptidesrepresented by the formula:L-pyroglutamyl-L-histidyl-L-trypyophyl-L-seryl-L-tyrosyl-X-Y-L-arginyl-L-prolyl-Zwherein X is D-tryptophyl, D-leucyl, D-alanyl, iminobenzyl-D-histidyl,3-(2-naphthyl)-D-alanyl, O-terbutyl-D-seryl, D-tyrosyl, D-lysyl,D-phenylalanyl or N-methyl-D-alanyl and Y is L-leucyl, D-leucyl, N.sup.α-methyl-D-leucyl, N.sup.α -methyl-L-leucyl or D-alanyl and wherein Z isglycyl-NHR₁ or NHR₁ wherein R₁ is H, lower alkyl or lower haloalkyl.Lower alkyl includes, for example, methyl, ethyl, propyl, pentyl,hexyls, iso-butyl, neopentyl and the like. Haloloweralkyl includes, forexample, --CF--₃, --CH₂ CF₃, --CF₂ CH₃, and the like. Fluorine is apreferred halogen.

Preferred nonapeptides wherein Y is L-leucyl and X is an opticallyactive D-form of selected amino acids and Z is NHC₂ H₅ are [D-Trp⁶,des-Gly-NH₂ ¹⁰ ]LHRH ethylamide (X=D-Trp⁶); [D-Ser-t-BuO)⁶, des-Gly-NH₂¹⁰ ]LHRH ethylamide [X-D-Ser(t-BuO⁶)]; [D-Leu⁶, des-Gly-NH₂ ¹⁰ ]LHRHethylamide (X=D-Leu⁶, [D-His(Bzl)⁶, des-Gly-NH₂ ¹⁰ ]LHRH ethylamide(X=iminobenzyl-D-His⁶) and [D-Ala⁶, des-Gly-NH₂ ¹⁰ ]-LHRH ethylamide(X=D-Ala⁶).

Preferred decapeptides include [D-Trp⁶ ]LHRH wherein X=D-Trp,Y=L-leucyl, Z=glycyl-NH₂, [D-Phe⁶ ]-LHRH wherein X=D-phenylalanyl,Y=L-leucyl and Z=glycyl-HN₂) or [D-Nal(2)⁶ LHRH which is [⁹³-3-(2-naphthyl)-D-Ala⁶ ]-LHRH wherein X=3(2-naphthyl)-D-alanyl,Y=L-leucyl and Z=glycyl-NH₂.

Other LHRH agonists useful within the scope of this invention are theα-aza analogues of the natural LHRH, especially, [D-Phe⁶, Azgly¹⁰ ]LHRH,[D-Tyr(--Me)⁶, Azgly¹⁰ ]LHRH, and [D-Ser-(t-BuO)⁶, Azgly¹⁰ ]LHRHdisclosed by A. S. Dutta et al. in J. Med. Chem., 21, 1018 (1978) andU.S. Pat. No. 4,100,274 as well as those disclosed in U.S. Pat. Nos.4,024,248 and 4,118,483.

Typical suitable LHRH antagonists include [N-Ac-D-p-Cl-Phe¹,², D-Phe³,D-Arg⁶, D-Ala¹⁰ ]-LHRH disclosed by J. Ercheggi et al., Biochem.Biophys. Res. Commun. 100, 915-920 (1981); [N-Ac-D-p-Cl-Phe¹,², D-Trp³,D-Arg⁶, D-Ala¹⁰ ]LHRH disclosed by D. H. Coy et al., Endocrinology, 110:1445-1447 (1982); [N-Ac-D-(3-(2-naphthyl)-OAla)¹, D-p-Cl-Phe², D-Trp³,D-hArg(Et₂)⁶, D-Ala¹⁰ ]LHRH and [N-Ac-Pro¹ ∵ D-pF-Phe²,D-(3-(2-naphthyl)-Ala³,⁶ ]-LHRH disclosed by J. J. Nestor et al. J.Steroid Biochem., 20 9no. 6B), 1366 (1984); the nona- and decapeptideanalogs of LHRH useful as LHRH antagonists disclosed in U.S. Pat. No.4,481,190 (J. J. Nestor et al.); analogs of the highly constrainedcyclic antagonist, cycle [Δ³ Pro¹, D-p-Cl-Phe², D-Trp³,⁶, N-Me-Leu⁷,β-Ala¹⁰ ]-LHRH disclosed by J. Rivier, J. Steroid Biochem., 20 (no. 6B),1365 (1984); and [N-Ac-D-(3-(2-naphthpyl)-Ala¹, D-p-F-Phe², D-Trp³,D-Arg⁶ ]LHRH disclosed by A. Corbin et al., J. Steroid Biochem. 20 (no.6B) 1369 (1984).

Preferred nonapeptides wherein Y is L-leucyl and X is an optionallyactive D-form of selected amino acids and Z is NHC₂ H₅ are [D-Trp⁶,des-Gly-NH₂ ¹⁰ ]LHRH ethylamide (X=D-Trp⁶); [D-Ser-t-BuO)⁶, des-Gly-NH₂¹⁰ ]LHRH ethylamide [X-D-Ser(t-BuO⁶)]; [D-Leu⁶, des-Gly-NH₂ ¹⁰ ]LHRHethylamide (X=D-Leu⁶, [D-His(Bzl)⁶, des-Gly-NH₂ ¹⁰ ]LHRH ethylamide(X=iminobenzyl-D-His⁶) and [D-Ala⁶, des-Gly-NH₂ ¹⁰ ]-LHRH ethylamide(X=D-Ala⁶).

Preferred decapeptides include [D-Trp⁶ ]LHRH wherein X=D-Trp,Y=L-leucyl, Z=glycyl-NH₂, [D-Phe⁶ ]-LHRH wherein X=D-phenylalanyl,Y=L-leucyl and Z=glycyl-HN₂) or [D-Nal(2)⁶ LHRH which is [⁹³-3-(2-naphthyl)-D-Ala⁶ ]LHRH wherein X=3(2-naphthyl)-D-alanyl,Y=L-leucyl and Z=glycyl-NH₂.

Other LHRH agonists useful within the scope of this invention are theα-aza analogues of the natural LHRH, especially, [D-Phe⁶, Azgly¹⁰ ]LHRH,[D-Tyr(--Me)⁶, Azgly¹⁰ ]LHRH, and [D-Ser-(t-BuO)⁶, Azgly¹⁰ ]LHRHdisclosed by A. S. Dutta et al. in J. Med. Chem., 21, 1081 (1978) andU.S. Pat. No. 4,100,274 as well as those disclosed in U.S. Pat. Nos.4,024,248 and 4,118,483.

Typical suitable LHRH antagonists include [N-Ac-D-p-Cl-Phe¹,², D-Phe³,D-Arg⁶, D-Ala¹⁰ ]-LHRH disclosed by J. Ercheggi et al., Biochem.Biophys. Res. Commun. 100, 915-920 (1981); [N-Ac-D-p-Cl-Phe¹,², D-Trp³,D-Arg⁶, D-Ala¹⁰ ]LHRH disclosed by D. H. Coy et al., Endocrinology, 110:1445-1447 (1982); [N-Ac-D-(3-(2-naphthyl)-OAla)¹, D-p-Cl-Phe², D-Trp³,D-hArg(Et₂)⁶, D-Ala¹⁰ ]LHRH and [N-Ac-Pro¹, D-pF-Phe²,D-(3-(2-naphthyl)-Ala³,⁶ ]-LHRH disclosed by J. J. Nestor et al. J.Steroid Biochem., 20 9no. 6B), 1366 (1984); the nona- and decapeptideanalogs of LHRH useful as LHRH antagonists disclosed in U.S. Pat. No.4,481,190 (J. J. Nestor et al.); analogs of the highly constrainedcyclic antagonist, cycle [Δ³ Pro¹, D-p-Cl-Phe², D-Trp³,⁶, N-Me-Leu⁷,β-Ala¹⁰ ]-LHRH disclosed by J. Rivier, J. Steroid Biochem., 20 (no. 6B),1365 (1984); and [N-Ac-D-(3-(2-naphthyl)-Ala¹, D-p-F-Phe², D-Trp³,D-Arg⁶ ]LHRH disclosed by A. Corbin et al., J. Steroid Biochem. 20 (no.6B) 1369 (1984).

Other LHRH agonist and antagonist analogs are disclosed in LHRH and itsanalogs (B. H. Vickery et al. eds, at pages 3-10 (J. J. Nestor), 11-22(J. Rivier et al.) and 22-33 (J. J. Nestor et al.) as well as in TheCase for LHRH agonists (Clinical Oncology, Furr and Denis, eds),Bailliere Tindall, vol. 2, no. 3, pp. 559-570, 1988).

The LHRH agonists and antagonists useful in this invention mayconveniently be prepared by the method described by Stewart et al. in"Solid Phase Peptide Synthesis" (published in 1969 by Freeman & Co., SanFrancisco, page 1) but solution phase synthesis may also be used.

The nona- and decapeptides used in this invention are convenientlyassembled on a solid resin support, such as 1% cross-linkedPro-merrifield resin by use of an automatic peptide synthesizer.Typically, side-chain protecting groups, well known to those in thepeptide arts, are used during the dicyclohexylcarbodiimidecatalyzedcoupling of a tert-butyloxycarbonylamino acid to the growing peptideattached to a benzhydrylamide resin. The tert-butyloxycarbonylprotecting groups are removed at each stage with trifluoroacetic acid.The nona- or decapeptide is cleaved from the resin and deprotected byuse of HF. The crude peptide is purified by the usual techniques, e.g.,gel filtration and partition chromatography and optionallylyophilization. See also D. H. Coy et al., J. Med. Chem. 19, pages423-425 (1976).

In this invention, the LHRH agonist or antagonist, the 5α-reductaseinhibitor, the antiandrogen, the antiestrogen, and, where applicable,the inhibitor of 3β- and 17β-hydroxysteroid dehydrogenase activities areadministered as pharmaceutical compositions via topical, parenteral ororal means. The LHRH agonist or antagonist is administered parenterally,i.e., intramuscularly, subcutaneously or intravenously by injection orinfusion by nasal drops or by suppository. The LHRH agonist orantagonist may also be microencapsulated in or attached to abiocompatable, biodegradable polymer, e.g.,poly(d,l-lactide-co-glycolide) and subcutaneously or intramuscularlyinjected by a technique called subcutaneous or intra-muscular depot toprovide continuous, slow release of the LHRH agonist or antagonist overa period of 30 days or longer. The most preferred route ofadministration of the LHRH agonist or antagonist is subcutaneous orintramuscular depot injection. Preferably the antiestrogen will beadministered orally. Preferably, the 5α-reductase inhibitor, theantiandrogen, the antiestrogen, the inhibitor of 3β-HSD and theinhibitor of 17β-HSD can also be administered orally. The antiestrogen,an inhibitor of 3β-HSD and inhibitor of 17β-HSD can also be administeredin a slow release formulation, e.g. poly(d,l-lactide-coglycolide) or asimplants.

The amount of each component administered is determined by the attendingclinicians taking into consideration the etiology and severity of thedisease, the patient's condition and age, the potency of each componentand other factors. According to this invention, the following dosageranges are suitable.

The LHRH agonist or antagonist is generally administered at from about10 to 5000 μg per day with contemplated dosage ranges of about 10 to1500 μg per day and about 250 (preferably 50 μg to 500 μg per day) forthe LHRH agonist and to about 100 to 2000 μg per day for the LHRHantogonist being preferred.

In the most preferred embodiment of this invention, the LHRH agonist orantagonist is administered subcutaneously in a daily dose of 500 μg forthe first 30 days and thereafter subcutaneously in a daily dose of 250μg regardless of the patients' body weight. When the LHRH agonist orantagonist is administered, once every 30-day period is used, with adose of 750 to 15,000 μg per 30-day period being preferred. Similardaily delivery doses are used for longer-term controlled releaseformulations.

The inhibitors of 3β-HSD and 17β-HSD are preferably administered indosages ranging from about 0.1 to 25 mg/kg per day with 200 mg per dayin two equally divided doses being preferred.

The antiestrogen compositions are administered in a dosage range ofabout 0.05 to 25 mg/kg body weight per day, with 20 mg, especially 40mg, in two equally divided doses being preferred.

The 5α-reductase inhibitor compositions are administered in a dosageranging from 0.1 to 25 mg/kg per day with 50 mg per day in twoequivalent doses being preferred.

The antiandrogen and aromatase inhibitor compositions are administeredin a dosage range of 0.5 to 25 mg/kg body weight per day with 750 mg perday in three equally divided doses being preferred.

The LHRH agonist or antagonist, antiestrogen, antiandrogen, an inhibitorof aromatase, 17β-HSD and 3β-HSD each may be administered separately orwhen the modes of administration are the same, all or at least two ofthem may be administered in the same composition, but in any case thepreferred ratio of LHRH agonist to antiestrogen, to antiandrogen toinhibitor of 17β-HSD and administered daily will be about 250 μg of LHRHagonist to about 750 mg of antiandrogen, about 40 mg of antiestrogen, toabout 40 mg of inhibitor of 17β-HSD and about 40 mg of inhibitor of3β-HSD.

In the therapy of prostate cancer, combining the administration of anLHRH agonist or antagonist, an antiestrogen, an antiandrogen and aninhibitor of 17β-HSD, the dosages preferable are as follows: the LHRHagonist or antagonist is generally administered at from about 10 to 2000μg per day, with contemplated dosage ranges of 10 to 500 μg per day,50-250 μg per day and 250 to 500 μg per day being preferred. In the mostpreferred embodiment of this aspect of this invention, the LHRH agonistor antagonist is administered subcutaneously in a daily dose of 500 μgfor the first 30 days and thereafter subcutaneously in a daily dose of250 μg regardless of the patients' body weight. When the LHRH agonist orantagonist is administered, once every 30-day period, by intramuscularor subcutaneous depot injection, a dose from about 300 to 60000(occasionally 10000) μg per 30-day period is used, with a dose of 750 to2000 μg per 30-day period being preferred. The antiandrogen compositionis generally administered in a dosage range of about 0.5 to 25 mg/kg(body weight) per day with 400 especially 750 mg per day in threeequally divided doses being preferred. The antiestrogen and inhibitor of17β-HSD and 3β-HSD activities are administered in a dosage range ofabout 0.1 to 25 mg/kg body weight per day, with 100 mg in two,preferably with 50 mg in two, equally divided doses being preferred.

The LHRH agonist or antagonist, antiandrogen, antiestrogen, 5α-reductaseinhibitor, inhibitor of 17β-HSD, inhibitor of 3β-HSD, inhibitor ofaromatase, each may be administered separately or when the modes ofadministration are the same, all or two or three of them may beadministered in the same composition, but in any case the preferredratio of LHRH agonist to antiandrogen to antiestrogen administered dailywill be about 750 μg of LHRH agonist to about 250 mg of antiandrogen topreferably 40 mg of antiestrogen.

In the therapy of prostate cancer, according to this invention, it ispreferred that the LHRH agonist is [D-Trp⁶, des-Gly-NH₂ ¹⁰ ]LHRHethylamide be administered subcutaneously in single daily dose of 500 μgfor the first thirty (30) days of treatment and thereafter in a singledaily dose of 250 μg.

In the combination therapy of prostate cancer according to thisinvention, the administration of the antiandrogen, antiestrogen,inhibitor of 17β-HSD, inhibitor of 5α-reductase, inhibitor of aromatase,and inhibitor of 3β-HSD, LHRH agonist or LHRH antagonist can be startedin any order of sequence. Preferably, the administration of theantiandrogen and 5α-reductase inhibitor, are started before (preferablytwo to four hours before) the administration of the LHRH agonist or LHRHantagonist is started. Orchiectomy can replace LHRH agonist orantagonist. Preferably, the administration of the inhibitor of 17β-HSDand inhibitor of 3β-HSD is started on the same day as the administrationof the LHRH agonist or LHRH antagonist. However, the attending clinicianmay elect to start administration of the LHRH agonist or antagonistsimultaneously with the antiandrogen, antiestrogen inhibitor of 17β-HSDand inhibitor of 3β-HSD.

When patients whose testes have already been surgically removed aretreated according to this invention, the administration and dosage ofthe antiandrogen and the other components of the therapy (except theLHRH agonist or antagonist which is not used) are the same as indicatedfor the therapy in which the LHRH agonist or antagonist is used.

The LHRH agonists or antagonists useful in the present invention aretypically amorphous solids which are freely soluble in water or diluteacids, e.g., HCl, H₂ SO₄, citric, acetic, mandelic or fumaric. The LHRHagonist or antagonist for subcutaneous injection is supplied in vialscontaining 5 ml of sterile solution with the LHRH agonist or antagonistat a concentration of about 1.0 mg/ml.

A typical pharmaceutical composition of the LHRH agonist or antagonistincludes the LHRH agonist or antagonist or a pharmaceutically acceptableacid salt thereof, benzyl alcohol, a phosphate buffer (pH 6.0-6.5) andsterile water.

The LHRH agonist or antagonist for intramuscular or subcutaneous depotinjection may be microencapsulated in a biocompatible, biodegradablepolymer, e.g., poly (d,l-lactide-co-glycolide) by a phase separationprocess or formed into a pellet. The microspheres may then be suspendedin a carrier to provide an injectable preparation or the depot may beinjected in the form of a pellet. See also European patent applicationEPA No. 58,481 published Aug. 25, 1982 for solid compositions forsubdermal injection or implantation or liquid formulations forintramuscular or subcutaneous injections containing biocompatible,biodegradable polymers such as lactide-glycolide copolymer and an LHRHagonist, e.g. D-Ser-t-BuO⁶, Azgly¹⁰ -LHRH. These formulations permitcontrolled release of the peptide.

The inhibitors of 17β-HSD, 3β-HSD, aromatase and 5α-reductase aretypically compounded in customary ways for oral administration, e.g., intablets, capsules and the like. These compounds useful in the presentinvention are typically formulated with conventional pharmaceuticalexcipients, e.g., spray dried lactose and magnesium stearate intotablets or capsules for oral administration. The antiestrogens, whenused with the invention, are typically compounded in customary ways fororal administration, e.g., in capsules, tablets, as dragees or even inliquid form, e.g., suspensions or syrups. One or more of the activesubstances, with or without additional types of active agents, can beworked into tablets or dragee cores by being mixed with solid,pulverulent carrier substances, such as sodium citrate, calciumcarbonate or dicalcium phosphate, and binders such as polyvinylpyrrolidone, gelatin or cellulose derivatives, possibly by adding alsolubricants such as magnesium stearate, sodium lauryl sulfate, "Carbowax"or polyethylene glycols. Of course, taste-improving substances can beadded in the case of oral administration forms.

The therapeutically active antiestrogen compound should be present in aconcentration of about 0.5-90% by weight of the total mixture, i.e., inamounts that are sufficient for maintaining the above-mentioned dosagerange.

As further forms, one can use plug capsules, e.g., of hard gelatin, aswell as closed soft-gelatin capsules comprising a softener orplasticizer, e.g. glycerine. The plug capsules contain the activesubstance preferably in the form of granulate, e.g., in mixture withfillers, such as lactose, saccharose, mannitol, starches, such as potatostarch or amylopectin, cellulose derivatives or highly-dispersed silicicacids. In soft-gelatin capsules, the active substance is preferablydissolved or suspended in suitable liquids, such as vegetable oils orliquid polyethylene glycols.

In place of oral administration, the active compounds may beadministered parenterally. In such case, one can use a solution of theactive substance, e.g., in sesame oil or olive oil. One or more of theactive substances (antiestrogen or inhibitor of 17β-HSD and 3β-HSD canbe microencapsulated in or attached to a biocompatible, biodegradablepolymer, e.g. poly(d,l-lactide-co-glycolide) and subcutaneously orintra-muscularly injected by a technique called subcutaneous orintramuscular depot to provide continuous slow release of thecompound(s) for a period of 2 weeks or longer.

In the most preferred aspect of this invention, the LHRH agonist is[D-Trp⁶,des-Gly-NH₂ ¹⁰ ] LHRH ethylamide which is administeredsubcutaneously in single daily dose of 500 μg for the first thirty (30)days of treatment and thereafter in a single daily dose of 250 μg: theantiandrogen is EM 101 which is administered orally in three equallydivided daily doses of 250 mg; and the inhibitor of sex steroidbiosynthesis is EM 139 and/or MK 906 administered orally in two equallydivided doses of 50 mg every 12 hours.

The inhibitor(s) of sex steroid biosynthesis and the antiandrogen arepreferably administered to a male in need of the prostate cancertreatment of this invention two to four hours before the LHRH agonist orantagonist is administered, but the at tending clinician may elect tostart administration of the LHRH agonist or antagonist, the antiandrogenand the inhibitor of steroid biosynthesis simultaneously. When theantiandrogen and sex steroid inhibitor are particularly effective, bothchemical (LHRH agonist or antagonist) and surgical castration may beavoided. Especially, when patients whose testes have already beensurgically removed are treated according to this invention, no LHRHagonist or antagonist need to be used but other dosages remain the same.

The terms and descriptions used herein are preferred embodiments setforth by way of illustration only, and are not intended as limitationson the many variations which those of skill in the art will recognize tobe possible in practicing the present invention as defined by thefollowing claims.

I claim:
 1. A method of treating prostate cancer in humans or otherwarm-blooded animals in need of such treatment, said method comprisingthe steps of blocking androgen receptors by administering atherapeutically effective amount of an antiandrogen having, as part ofits molecular structure, a substituted or unsubstituted androgenicnucleus of the formula: ##STR14## having a non-aromatic A ring andhaving as another part of its molecular structure, at least one sidechain represented by the formula:--R¹ (--B--R² --)_(x) L--G said chainbeing substituted onto said androgenic nucleus at a position selectedfrom the group consisting of 6, 7, 14, 15, 16 and 17, wherein:x is aninteger from 0 to 6, wherein at least one of L and G is a polar moietydistanced from said ring carbon by at least three intervening atoms, andwherein: R¹ and R² are independently either absent or selected from thegroup consisting of straight- or branched-chain alkylene, straight- orbranched-chain alkynlene, straight- or branched-chain alkenylene,phenylene and fluoro-substituted analogs of the foregoing; B is eitherabsent or selected from the group consisting of --O--, --S--, --Se--,--SO₃ --, --SO₂ --, NR³ --, SiR₂ ³ --, CR³ OR³ --, NR³ CO--, --NR³ CS--,--CONR³ --, CSNR³ --, --COO--, --COS--, --SCO--, --CSS--, --SCS--,--OCO-- and phenylene (R³ being hydrogen or lower alkyl); L is selectedfrom the group consisting of lower alkyl, --CONR⁴ --, --CSNR⁴ --, --NR⁵CO--, NR⁵ CS--, --NR⁵ CONR⁴ -- ##STR15## --SO₂ --NR⁴ --, --CSS--,--SCS--, --(NO)R⁴ --, --(PO)R⁴ --, --NR⁵ COO--, --NR⁵ SO₂ --, --O--,--NR⁴ --, --S--, --SO-- and --SO₂ -- (R⁴ and R⁵ being independentlyselected from the group consisting of hydrogen and lower alkyl; and R⁶being selected from the group consisting of hydrogen, nitrile andnitro); and G is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, (C₃ -C₇)cycloalkyl,bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,cyano(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl, and fluoro-substituted analogs of theforegoing; said method of treatment further comprising the step ofinhibiting sex steroid formation by administering a therapeuticallyeffective amount of at least one additional compound that is a sexsteroid formation inhibitor whose mechanism of inhibition is other thansuppression of adrenal activity.
 2. The method of claim 1 wherein saidinhibition of sex steroid synthesis includes administering atherapeutically effective amount of an inhibitor of 5α-reductase.
 3. Themethod of claim 1 wherein said inhibition of sex steroid synthesisincludes administering a therapeutically effective amount of aninhibitor of 17β-hydroxysteroid dehydrogenase.
 4. The method of claim 1wherein said inhibition of sex steroid synthesis includes administeringa therapeutically effective amount of an inhibitor of 5α-reductase andan inhibitor of 17β-hydroxysteroid dehydrogenase.
 5. The methodaccording to claim 1 further comprising the step of administering atherapeutically effective amount of an antiestrogen.
 6. The methodaccording to claim 2 further comprising the step of administering atherapeutically effective amount of an antiestrogen.
 7. The methodaccording to claim 3 further comprising the step of administering atherapeutically effective amount of an antiestrogen.
 8. The methodaccording to claim 4 further comprising the step of administering atherapeutically effective amount of an antiestrogen.
 9. The method ofclaim 1 wherein said inhibition includes the step of administering amixture of sex steroid inhibitors which together are capable ofinhibiting the function of 5α-reductase and the function of17β-hydroxysteroid dehydrogenase and the function of 3β-hydroxysteroiddehydrogenase.
 10. The method according to claim 9 further comprisingthe step of administering a therapeutically effective amount of anantiestrogen.
 11. The method of claim 1 further comprising the step ofinhibiting testicular hormonal secretion of said warm-blooded animal.12. The method of claim 11 wherein said testicular hormonal secretion isinhibited by at least one technique selected from the group consistingof surgical castration, administration of an antagonist of luteinizinghormone releasing hormone, and administration of an agonist ofluteinizing hormone releasing hormone.
 13. The method of claim 1 whereinsaid inhibition of sex steroid synthesis includes the step ofadministering an inhibitor of 5α-reductase activity, and wherein saidmethod further includes inhibiting the testicular hormonal secretion ofsaid warm-blooded animal.
 14. A method of treating prostate cancer inhumans or other warm-blooded animals in need of such treatment, saidmethod comprising the steps of blocking androgen receptors byadministering a therapeutically effective amount of an antiandrogenhaving, as part of its molecular structure, a substituted orunsubstituted androgenic nucleus of the formula: ##STR16## having anon-aromatic A ring and having as another part of its molecularstructure, at least one side chain represented by the formula:--R¹ _(x)L--G said chain being substituted onto said androgenic nucleus at aposition selected from the group consisting of 6, 7, 14, 15, 16 and 17,wherein: x is an integer from 0 to 6, wherein at least one of L and G isa polar moiety distanced from said ring carbon by at least threeintervening atoms, and wherein: R¹ and R² are independently eitherabsent or selected from the group consisting of straight- orbranched-chain alkylene, straight- or branched-chain alkynylene,straight- or branched-chain alkenylene, phenylene and fluoro-substitutedanalogs of the foregoing; B is either absent or selected from the groupconsisting of --O--, --S--, --Se--, --SO--, --SO₂ --, --NR³ --, --SiR₂ ³--, --CR³ OR³ --, --NR³ CO--, NR³ CS--, --CONR³ --, --CSNR³ --, --COO--,--COS--, --SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R³ beinghydrogen or lower alkyl); L is selected from the group consisting oflower alkyl --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵ CS--, --NR⁵ CONR⁴--, ##STR17## --SO₂ NR⁴ --, --CSS--, --SCS--, --(NO)R⁴ --, --(PO)R⁴ --,--NR⁵ COO--, --NR⁵ SO₂ --, --O--, --NR⁴ --, --S--, --SO-- and --SO₂ --(R⁴ and R⁵ being independently selected from the group consisting ofhydrogen and lower alkyl; and R⁶ being selected from the groupconsisting of hydrogen, nitrile and nitro); and G is selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynl,(C₃ -C₇) cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl, and fluoro-substituted analogs of theforegoing; said method of treatment further comprising the step ofinhibiting sex steroid activity formation by administering atherapeutically effective amount of at least one sex steroid formationinhibitor selected from the group consisting of: N-butyl,N-methyl-11-(16'α-chloro-3', 17'β-dihydroxy estra-1', 3', 5'(10')-trien-7'α-yl) undecanamide ("EM 139"): ##STR18## ##STR19##N-n-butyl-N-methyl-11-(16'α-bromo-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl) undecanamide ("EM171"): ##STR20## wherein R is either hydrogen or ethynl.
 15. The methodof claim 14, said method further including inhibiting testicular hormonesecretion of said warm-blooded animal.
 16. A method for treatingprostrate cancer in humans or other warm blooded animals in need of suchtreatment said method comprising the step of blocking androgen receptorsby administering a therapeutically amount of an antiandrogen representedby the formula: ##STR21## wherein the dotted line represents an optionaldouble bond; x is 0, R¹ is (--CH₂ --)₂ (with y being an integer from 4to 20), R¹⁷(α) is hydrogen, lower alkyl or a moiety which together withR¹⁷(β) forms: ##STR22## wherein R¹⁷(β) is selected from the groupconsisting of hydrogen, hydroxyl, lower alkyl, acyloxy, and a moietywhich, together with R¹⁷(α) forms: ##STR23## wherein said treatmentfurther comprises the step of inhibiting sex steroid formation byadministering a therapeutically effective amount of at least oneadditional compound that is a sex steroid formation inhibitor.
 17. Themethod of claim wherein said antiandrogen is represented by the formula:##STR24## wherein the dotted lines represent optional double bonds;wherein R¹⁰ is hydrogen or lower alkyl, R¹³ is absent, hydrogen ormethyl in β position,R¹⁷(α) is selected from the group consisting ofhydrogen, hydroxyl, lower alkanoyloxy, lower alkyl, lower alkenyl, loweralkynyl, halo(lower)alkyl, halo(lower)alkenyl, halo(lower)alkynyl andfluoro-substituted aromatic ring, and a moiety which, together withR¹⁷(β) forms ##STR25## R¹⁷(β) is selected from the group consisting ofhydroxyl, (C₁ -C₂₀) alkanoyloxy, (C₃ -C₇)alkenoyloxy, (C₃ -C₇)alkynoyloxy, aroyloxy, alkenoyloxy, cycloalkenyloxy, 1alkyloxy-alkyloxy,1-alkyloxycycloalkyloxy, alkyl-, ##STR26## silyloxy, carboxyl, alkanoyland a moiety which together with R¹⁷ forms ##STR27##
 18. The method ofclaim 1 wherein said antiandrogen is represented by the formula:##STR28## wherein the AB-ring junction is trans, the dotted linesrepresent optional pi bonds; wherein y is an integer from 4 to 20,wherein L is selected from the group consisting of --CONR⁴ --, --CSNR⁴--, --NR⁵ CO--, --NR⁵ CS-- and --CH² -- (R⁴ and R⁵ being hydrogen ormethyl) and G is selected from the group consisting of n-propyl,n-butyl, n-pentyl and haloalkyl.
 19. A method of treating prostatecancer in humans or other warm-blooded animals in need of suchtreatment, said method comprising the step of blocking androgenreceptors by administering a therapeutically effective amount of anantiandrogen having, as part of its molecular structure, a substitutedor unsubstituted androgenic nucleus of the formula: ##STR29## having anon-aromatic A ring and having as another part of its molecularstructure, at least one side chain represented by the formula:--R¹(--B--R² --)_(x) L-G said chain being substituted onto said androgenicnucleus at a position selected from the group consisting of 6, 7, 14,15, 16 and 17, wherein:x is an integer from 0 to 6, wherein at least oneof L and G is a polar moiety distanced from said ring carbon by at leastthree intervening atoms, and wherein: R¹ and R² are independently eitherabsent or selected from the group consisting of straight- orbranched-chain alkylene, straight- or branched-chain alkynylene,straight- or branched-chain alkenylene, phenylene and fluoro-substitutedanalogs of the foregoing; B is either absent or selected from the groupconsisting of --O--, --S--, --Se--, --SO--, --SO₂ --, --NR³ --, --SiR³ ₂--, --CR³ OR³ --, --NR³ CO--, NR³ CS--, --CONR³ --, --CSNR³ --, --COO--,--COS--, --SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R³ beinghydrogen or lower alkyl); L is selected from the group consisting oflower alkyl --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵ CS--, --NR⁵ CONR⁴--, ##STR30## --SO₂ NR⁴ --, --CSS--, --SCS--, --(NO)R⁴ --, --(PO)R⁴ --,--NR⁵ COO--, --NR⁵ SO₂ --, --O--, --NR⁴ --, --S--, --SO-- and --SO₂ --(R⁴ and R⁵ being independently selected from the group consisting ofhydrogen and lower alkyl; and R⁶ being selected from the groupconsisting of hydrogen, nitrile and nitro); and G is selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl,(C₃ -C₇) cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl, and fluoro-substituted analogs of theforegoing; said method of treatment further comprising the step ofinhibiting sex steroid activity formation by administering atherapeutically effective amount of at least one non-adrenal sex steroidformation inhibitor; wherein said sex steroid formation inhibitor isselected from a group consisting of an inhibitor of 3β-hydrogenase, aninhibitor of 17β-hydroxysteroid dehydrogenase, an inhibitor of5α-reductase and an inhibitor of aromatase.
 20. The method of claim 19,wherein said sex steroid formation inhibitor is an inhibitor of3β-hydroxysteroid dehydrogenase.
 21. The method of claim 19, whereinsaid sex steroid formation inhibitor is an inhibitor of aromatase.
 22. Amethod of treating prostate cancer in humans or other warm-bloodedanimals in need of such treatment, said method comprising the steps ofblocking androgen receptors by administering a therapeutically effectiveamount of an antiandrogen having, as part of its molecular structure, asubstituted or unsubstituted androgenic nucleus of the formula:##STR31## having a non-aromatic A ring and having as another part of itsmolecular structure, at least one side chain represented by theformula:--R¹ (--B--R² --)_(x) L-G said chain being substituted onto saidandrogenic nucleus at a position selected from the group consisting of6, 7, 14, 15, 16 and 17, wherein:x is an integer from 0 to 6, wherein atleast one of L and G is a polar moiety distanced from said ring carbonby at least three intervening atoms, and wherein: R¹ and R² areindependently either absent or selected from the group consisting ofstraight- or branched-chain alkylene, straight- or branched-chainalkynylene, straight- or branched-chain alkenylene, phenylene andfluoro-substituted analogs of the foregoing; B is either absent orselected from the group consisting of --O--, --S--, --Se--, --SO--,--SO₂ --, --NR³ --, --SiR³ ₂ --, --CR³ OR³ --, --NR³ CO--, NR³ CS--,--CONR³ --, --CSNR³ --, --COO--, --COS--, --SCO--, --CSS--, --SCS--,--OCO-- and phenylene (R³ being hydrogen or lower alkyl); L is selectedfrom the group consisting of lower alkyl --CONR⁴ --, --CSNR⁴ --, --NR⁵CO--, --NR⁵ CS--, --NR⁵ CONR⁴ --, ##STR32## --SO₂ NR⁴ --, --CSS--,--SCS--, --(NO)R⁴ --, --(PO)R⁴ --, --NR⁵ COO--, --NR⁵ SO₂ --, --O--,--NR⁴ --, --S--, --SO-- and --SO₂ -- (R⁴ and R⁵ being independentlyselected from the group consisting of hydrogen and lower alkyl; and R⁶being selected from the group consisting of hydrogen, nitrile andnitro); and G is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, (C₃ -C₇) cycloalkyl,bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,cyano(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl, and fluoro-substituted analogs of theforegoing; said method of treatment further comprising the step ofinhibiting sex steroid activity formation by administering atherapeutically effective amount of at least one non-adrenal sex steroidformation inhibitor;wherein said inhibitor of sex steroid formation is:##STR33## wherein R is either hydrogen or ethynyl.
 23. The method ofclaim 1, wherein said sex steroid formation inhibitor is an aromataseinhibitor.
 24. The method of claim 2, wherein said inhibitor of5α-reductase is Proscar.
 25. The method of claim 1, wherein L isselected from the group consisting of --CONR⁴ --, --O--, --NR⁴ --,--S--, --SO-- and --SO₂ --(R⁴ being hydrogen or lower alkyl); andwhereinG is selected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, (C₃ -C₇)cycloalkyl, bromo(lower)alkyl,chloro(lower)alkyl, fluoro(lower)alkyl, cyano(lower)alkyl,carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl,(C₇ -C₁₁)arylalkyl, di(lower)alkylamino(lower)alkyl.
 26. The method ofclaim 25, wherein L is --CONR⁴ --.
 27. The method of claim 25, wherein Gis selected from the group consisting of lower alkyl, bromo(lower)alkyl,chloro(lower)alkyl and fluoro(lower)alkyl.
 28. The method of claim 27,where L is --CONR⁴ --.
 29. The method of claim 13, wherein testicularhormonal secretion is inhibited by administering an LHRH agonist orantagonist.